Scholars@Duke
Donald Patrick McDonnell

Donald Patrick McDonnell

Glaxo-Wellcome Distinguished Professor of Molecular Cancer Biology, in the School of Medicine
Pharmacology & Cancer Biology
donald.mcdonnell@duke.edu
Duke Box 3813, Durham, NC 27710
2138 MSRB3, 3 Genome Ct., Durham, NC 27710

Selected Publications

The Roles of Natural Killer Cells in Breast Cancer Pathobiology and their Regulation by Estrogens.

Journal Article Endocr Rev · May 9, 2025 Breast cancer remains the most commonly diagnosed malignancy among women worldwide. While breast cancer treatment outcomes have improved in recent years there remains an unmet medical need for therapeutics that can be used with curative intent in the most ... Full text Link to item Cite

Thienopyridine Based Estrogen Receptor Modulators Adopt Unique Ligand Binding Poses to Elicit Anti Proliferative Activities in ER + Breast Cancer Cells

Conference Endocrinology · April 21, 2025 Abstract TextOne in eight women will be diagnosed with breast cancer in their lifetimes. Estrogen receptor alpha (ER) drives breast cancer pathology and is expressed in approximately seventy percent of tumor ... Full text Cite

PKN2 Is a Dependency of the Mesenchymal-like Cancer Cell State.

Journal Article Cancer Discov · March 3, 2025 Cancer cells exploit a mesenchymal-like transcriptional state (MLS) to survive drug treatments. Although the MLS is well characterized, few therapeutic vulnerabilities targeting this program have been identified. In this study, we systematically identify t ... Full text Link to item Cite

ESRRA (estrogen related receptor, alpha) induces ribosomal protein RPLP1-mediated adaptive hepatic translation during prolonged starvation.

Journal Article Autophagy · February 18, 2025 Protein translation is an energy-intensive ribosome-driven process that is reduced during nutrient scarcity to conserve cellular resources. During prolonged starvation, cells selectively translate specific proteins to enhance their survival (adaptive trans ... Full text Link to item Cite

Mitoxantrone inhibits and downregulates ER α through binding at the DBD-LBD interface.

Journal Article bioRxiv · January 8, 2025 Targeting the estrogen receptor (ER or ERα) through competitive antagonists, receptor downregulators, or estrogen synthesis inhibition remains the primary therapeutic strategy for luminal breast cancer. We have identified a novel mechanism of ER inhibition ... Full text Link to item Cite

Effects of RARα ligand binding domain mutations on breast fibroepithelial tumor function and signaling.

Journal Article NPJ Breast Cancer · January 3, 2025 Point mutations in the ligand binding domain of retinoic acid receptor alpha (RARα) are linked to breast fibroepithelial tumor development, but their role in solid tumorigenesis is unclear. In this study, we assessed the functional effects of known RARα mu ... Full text Link to item Cite

The EstroGene2.0 database for endocrine therapy response and resistance in breast cancer.

Journal Article NPJ Breast Cancer · December 19, 2024 Endocrine therapies targeting the estrogen receptor (ER/ESR1) are the cornerstone to treat ER-positive breast cancers patients, but resistance often limits their effectiveness. Notable progress has been made although the fragmented way data is reported has ... Full text Link to item Cite

7993 Thienopyrimidine-Based Estrogen Receptor Modulators Adopt Unique Ligand Binding Poses to Elicit Anti-Proliferative Activities in ER+ Breast Cancer Cells

Conference Journal of the Endocrine Society · October 5, 2024 AbstractDisclosure: E.C. Fink: None. S.L. Mateus: None. N. Meganathan: None. V.K. Sammeta: None. J.D. Norris: None. D.P. McDonnell: None. T. Willson: None. S.W. Fanning: None. Full text Cite

Estrogen signaling suppresses tumor-associated tissue eosinophilia to promote breast tumor growth.

Journal Article Sci Adv · September 27, 2024 Estrogens regulate eosinophilia in asthma and other inflammatory diseases. Further, peripheral eosinophilia and tumor-associated tissue eosinophilia (TATE) predicts a better response to immune checkpoint blockade (ICB) in breast cancer. However, how and if ... Full text Link to item Cite

Data from Targeting CaMKK2 inhibits actin cytoskeletal assembly to suppress cancer metastasis

Other · September 16, 2024 <div>Abstract<p>Triple-negative breast cancers (TNBCs) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early stage localized TNBC, the rate of distant recurrence remains h ... Full text Cite

Supplementary Figures 1-4 and Tables 1-2 from Targeting CaMKK2 inhibits actin cytoskeletal assembly to suppress cancer metastasis

Other · September 16, 2024 <p>Contains Supplementary Figures 1-4, Supplementary Tables 1-2 and legends for Supplementary Videos 1-4</p> ... Full text Cite

Data from Targeting CaMKK2 inhibits actin cytoskeletal assembly to suppress cancer metastasis

Other · September 16, 2024 <div>Abstract<p>Triple-negative breast cancers (TNBCs) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early stage localized TNBC, the rate of distant recurrence remains h ... Full text Cite

Supplementary Figures 1-4 and Tables 1-2 from Targeting CaMKK2 inhibits actin cytoskeletal assembly to suppress cancer metastasis

Other · September 16, 2024 <p>Contains Supplementary Figures 1-4, Supplementary Tables 1-2 and legends for Supplementary Videos 1-4</p> ... Full text Cite

Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in metabolic dysfunction-associated steatohepatitis and reversed by alternate day fasting.

Journal Article Mol Metab · September 2024 OBJECTIVE: Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH). METHODS: Unbiased label ... Full text Link to item Cite

Androgen receptor monomers and dimers regulate opposing biological processes in prostate cancer cells.

Journal Article Nature communications · September 2024 Most prostate cancers express the androgen receptor (AR), and tumor growth and progression are facilitated by exceptionally low levels of systemic or intratumorally produced androgens. Thus, absolute inhibition of the androgen signaling axis remains the go ... Full text Cite

EstroGene2.0: A multi-omic database of response to estrogens, ER-modulators, and resistance to endocrine therapies in breast cancer.

Journal Article bioRxiv · July 2, 2024 Endocrine therapies targeting the estrogen receptor (ER/ESR1) are the cornerstone to treat ER-positive breast cancers patients, but resistance often limits their effectiveness. Understanding the molecular mechanisms is thus key to optimize the existing dru ... Full text Link to item Cite

The Impact of Circulating Tumor Cell HOXB13 RNA Detection in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Abiraterone or Enzalutamide.

Conference Clin Cancer Res · March 15, 2024 PURPOSE: HOXB13 is an androgen receptor (AR) coregulator specifically expressed in cells of prostatic lineage. We sought to associate circulating tumor cell (CTC) HOXB13 expression with outcomes in men with mCRPC treated with abiraterone or enzalutamide. E ... Full text Link to item Cite

Supplementary Table S2 from The Impact of Circulating Tumor Cell HOXB13 RNA Detection in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Abiraterone or Enzalutamide

Other · March 15, 2024 <p>Association of CTC HOXB13 expression with overall survival, univariate and multivariate analysis including adjustment for JHU CTC AR-V7 status</p> ... Full text Cite

Supplementary Table S2 from The Impact of Circulating Tumor Cell HOXB13 RNA Detection in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Abiraterone or Enzalutamide

Other · March 15, 2024 <p>Association of CTC HOXB13 expression with overall survival, univariate and multivariate analysis including adjustment for JHU CTC AR-V7 status</p> ... Full text Cite

Data from The Impact of Circulating Tumor Cell HOXB13 RNA Detection in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Abiraterone or Enzalutamide

Other · March 15, 2024 <div>AbstractPurpose:<p>HOXB13 is an androgen receptor (AR) coregulator specifically expressed in cells of prostatic lineage. We sought to associate circulating tumor cell (CTC) HOXB13 expression with outcomes in men with mCRPC treated ... Full text Cite

Data from The Impact of Circulating Tumor Cell HOXB13 RNA Detection in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Abiraterone or Enzalutamide

Other · March 15, 2024 <div>AbstractPurpose:<p>HOXB13 is an androgen receptor (AR) coregulator specifically expressed in cells of prostatic lineage. We sought to associate circulating tumor cell (CTC) HOXB13 expression with outcomes in men with mCRPC treated ... Full text Cite

Estrogen receptor-related receptor (Esrra) induces ribosomal protein Rplp1-mediated adaptive hepatic translation during prolonged starvation.

Journal Article bioRxiv · January 10, 2024 Protein translation is an energy-intensive ribosome-driven process that is reduced during nutrient scarcity to conserve cellular resources. During prolonged starvation, cells selectively translate specific proteins to enhance their survival (adaptive trans ... Full text Link to item Cite

Identification of Small Molecule Inhibitors and Ligand Directed Degraders of Calcium/Calmodulin Dependent Protein Kinase Kinase 1 and 2 (CaMKK1/2).

Journal Article J Med Chem · December 14, 2023 CaMKK2 signals through AMPK-dependent and AMPK-independent pathways to trigger cellular outputs including proliferation, differentiation, and migration, resulting in changes to metabolism, bone mass accrual, neuronal function, hematopoiesis, and immunity. ... Full text Link to item Cite

Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis.

Journal Article Cancer Res · September 1, 2023 UNLABELLED: Triple-negative breast cancers (TNBC) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early-stage localized TNBC, the rate of distant recurrence remains high, and long-term surviv ... Full text Link to item Cite

Structural Determinants of the Binding and Activation of Estrogen Receptor α by Phenolic Thieno[2,3-d]pyrimidines

Journal Article Helvetica Chimica Acta · September 1, 2023 Synthetic, structural, and computational approaches were used to solve the puzzle as to how a phenolic nonsteroidal estrogen 1 with only a single H-bond to its receptor was more potent than an isomer 2 which formed an intricate network of H-bonds. Synthesi ... Full text Cite

Supplementary Figures 1-4 and Tables 1-2 from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis

Other · September 1, 2023 <p>Contains Supplementary Figures 1-4, Supplementary Tables 1-2 and legends for Supplementary Videos 1-4</p> ... Full text Cite

Supplementary Figures 1-4 and Tables 1-2 from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis

Other · September 1, 2023 <p>Contains Supplementary Figures 1-4, Supplementary Tables 1-2 and legends for Supplementary Videos 1-4</p> ... Full text Cite

Data from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis

Other · September 1, 2023 <div>Abstract<p>Triple-negative breast cancers (TNBC) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early-stage localized TNBC, the rate of distant recurrence remains hi ... Full text Cite

Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice.

Journal Article Nat Commun · July 25, 2023 Hypercholesterolemia and vascular inflammation are key interconnected contributors to the pathogenesis of atherosclerosis. How hypercholesterolemia initiates vascular inflammation is poorly understood. Here we show in male mice that hypercholesterolemia-dr ... Full text Link to item Cite

Data from Increased CaMKK2 Expression Is an Adaptive Response That Maintains the Fitness of Tumor-Infiltrating Natural Killer Cells

Other · April 4, 2023 <div>Abstract<p>Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression ... Full text Cite

Data from Increased CaMKK2 Expression Is an Adaptive Response That Maintains the Fitness of Tumor-Infiltrating Natural Killer Cells

Other · April 4, 2023 <div>Abstract<p>Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression ... Full text Cite

ABL kinases regulate the stabilization of HIF-1α and MYC through CPSF1.

Journal Article Proceedings of the National Academy of Sciences of the United States of America · April 2023 The hypoxia-inducible factor 1-α (HIF-1α) enables cells to adapt and respond to hypoxia (Hx), and the activity of this transcription factor is regulated by several oncogenic signals and cellular stressors. While the pathways controlling normoxic degradatio ... Full text Open Access Cite

Estrogen Receptor Signaling in the Immune System.

Journal Article Endocr Rev · January 12, 2023 The immune system functions in a sexually dimorphic manner, with females exhibiting more robust immune responses than males. However, how female sex hormones affect immune function in normal homeostasis and in autoimmunity is poorly understood. In this rev ... Full text Link to item Cite

SGC-CAMKK2-1: A Chemical Probe for CAMKK2.

Journal Article Cells · January 11, 2023 The serine/threonine protein kinase calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays critical roles in a range of biological processes. Despite its importance, only a handful of inhibitors of CAMKK2 have been disclosed. Having a selectiv ... Full text Open Access Link to item Cite

Increased CaMKK2 Expression Is an Adaptive Response That Maintains the Fitness of Tumor-Infiltrating Natural Killer Cells.

Journal Article Cancer Immunol Res · January 3, 2023 Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression in tumor-associated immune cells fac ... Full text Link to item Cite

Eosinophilia in cancer and its regulation by sex hormones.

Journal Article Trends Endocrinol Metab · January 2023 Gender differences in the functionality of the immune system have been attributed, in part, to direct and indirect effects of sex steroids, especially estrogens, on immune cell repertoire and activity. Notable are studies that have defined roles for estrog ... Full text Link to item Cite

Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor-Positive Breast Cancer.

Journal Article Clin Cancer Res · December 1, 2022 PURPOSE: Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from the combination of palbociclib plus ET in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer. Bazedoxifene is a third-generation selective estr ... Full text Link to item Cite

Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma.

Journal Article Nat Commun · October 29, 2022 Glioblastoma (GBM) is notorious for its immunosuppressive tumor microenvironment (TME) and is refractory to immune checkpoint blockade (ICB). Here, we identify calmodulin-dependent kinase kinase 2 (CaMKK2) as a driver of ICB resistance. CaMKK2 is highly ex ... Full text Link to item Cite

PPAR agonists attenuate lenalidomide's anti-myeloma activity in vitro and in vivo.

Journal Article Cancer Lett · October 1, 2022 Many patients with multiple myeloma (MM) have comorbidities and are treated with PPAR agonists. Immunomodulatory agents (IMiDs) are the cornerstones for MM therapy. Currently, little is known about how co-administration of PPAR agonists impacts lenalidomid ... Full text Link to item Cite

Development and Characterization of a Luciferase Labeled, Syngeneic Murine Model of Ovarian Cancer.

Journal Article Cancers (Basel) · August 30, 2022 Despite advances in surgery and targeted therapies, the prognosis for women with high-grade serous ovarian cancer remains poor. Moreover, unlike other cancers, immunotherapy has minimally impacted outcomes in patients with ovarian cancer. Progress in this ... Full text Open Access Link to item Cite

A New Chemotype of Chemically Tractable Nonsteroidal Estrogens Based on a Thieno[2,3-d]pyrimidine Core.

Journal Article ACS Med Chem Lett · July 14, 2022 Despite continued interest in the development of nonsteroidal estrogens and antiestrogens, there are only a few chemotypes of estrogen receptor ligands. Using targeted screening in a ligand sensing assay, we identified a phenolic thieno[2,3-d]pyrimidine wi ... Full text Link to item Cite

Current and emerging estrogen receptor-targeted therapies for the treatment of breast cancer.

Journal Article Essays Biochem · December 17, 2021 Nearly 80% of all breast cancers are estrogen receptor positive (ER+) and require the activity of this transcription factor for tumor growth and survival. Thus, endocrine therapies, which target the estrogen signaling axis, have and will continue to be the ... Full text Link to item Cite

Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma.

Journal Article J Clin Invest · December 1, 2021 Immune checkpoint blockade (ICB) therapies have significantly prolonged patient survival across multiple tumor types, particularly in melanoma. Interestingly, sex-specific differences in response to ICB have been observed, with males receiving a greater be ... Full text Open Access Link to item Cite

Mechanistic Investigation of Site-specific DNA Methylating Agents Targeting Breast Cancer Cells.

Journal Article J Med Chem · September 9, 2021 We previously described the development of a DNA-alkylating compound that showed selective toxicity in breast cancer cells. This compound contained an estrogen receptor α (ERα)-binding ligand and a DNA-binding/methylating component that could selectively m ... Full text Link to item Cite

Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer.

Journal Article Nat Commun · August 24, 2021 Hypercholesterolemia and dyslipidemia are associated with an increased risk for many cancer types and with poor outcomes in patients with established disease. Whereas the mechanisms by which this occurs are multifactorial we determine that chronic exposure ... Full text Link to item Cite

The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor.

Journal Article Mol Cancer Ther · July 2020 The estrogen receptor (ER/ESR1) is expressed in a majority of breast cancers and drugs that inhibit ER signaling are the cornerstone of breast cancer pharmacotherapy. Currently, aromatase inhibitors are the frontline endocrine interventions of choice altho ... Full text Link to item Cite

Correction to: Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy.

Journal Article Breast Cancer Res Treat · February 2020 The article Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy, written by Suzanne E. Wardell, Alexander P. Yllanes, ... Full text Link to item Cite

Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy.

Journal Article Breast cancer research and treatment · January 2020 PurposeFulvestrant is a selective estrogen receptor downregulator (SERD) that is approved for first- or second-line use as a single agent or in combination with cyclin dependent kinase or phosphatidylinositol 3-kinase inhibitors for the treatment ... Full text Cite

The Signaling Pathways Project, an integrated 'omics knowledgebase for mammalian cellular signaling pathways.

Journal Article Sci Data · October 31, 2019 Mining of integrated public transcriptomic and ChIP-Seq (cistromic) datasets can illuminate functions of mammalian cellular signaling pathways not yet explored in the research literature. Here, we designed a web knowledgebase, the Signaling Pathways Projec ... Full text Link to item Cite

The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer.

Journal Article Cell Rep · October 22, 2019 Notwithstanding the positive clinical impact of endocrine therapies in estrogen receptor-alpha (ERα)-positive breast cancer, de novo and acquired resistance limits the therapeutic lifespan of existing drugs. Taking the position that resistance is nearly in ... Full text Link to item Cite

Constitutively active ESR1 mutations in gynecologic malignancies and clinical response to estrogen-receptor directed therapies.

Journal Article Gynecol Oncol · July 2019 OBJECTIVE: Endocrine therapy is often considered as a treatment for hormone-responsive gynecologic malignancies. In breast cancer, activating mutations in the estrogen receptor (mutESR1) contribute to therapeutic resistance to endocrine therapy, especially ... Full text Link to item Cite

Inhibition of ERRα Prevents Mitochondrial Pyruvate Uptake Exposing NADPH-Generating Pathways as Targetable Vulnerabilities in Breast Cancer.

Journal Article Cell Rep · June 18, 2019 Most cancer cells exhibit metabolic flexibility, enabling them to withstand fluctuations in intratumoral concentrations of glucose (and other nutrients) and changes in oxygen availability. While these adaptive responses make it difficult to achieve clinica ... Full text Link to item Cite

CaMKK2 in myeloid cells is a key regulator of the immune-suppressive microenvironment in breast cancer.

Journal Article Nat Commun · June 4, 2019 Tumor-associated myeloid cells regulate tumor growth and metastasis, and their accumulation is a negative prognostic factor for breast cancer. Here we find calcium/calmodulin-dependent kinase kinase (CaMKK2) to be highly expressed within intratumoral myelo ... Full text Link to item Cite

Decoding the Inversion Symmetry Underlying Transcription Factor DNA-Binding Specificity and Functionality in the Genome.

Journal Article iScience · May 31, 2019 Understanding why a transcription factor (TF) binds to a specific DNA element in the genome and whether that binding event affects transcriptional output remains a great challenge. In this study, we demonstrate that TF binding in the genome follows inversi ... Full text Link to item Cite

Combination mTORC1/2 and BCL- XL inhibition in endocrine and CDK4/6-resistant estrogen receptor-positive breast cancer.

Conference Journal of Clinical Oncology · May 20, 2019 e14653 Background: Endocrine therapy plus CDK 4/6 inhibition has led to impressive improvements in progression-free survival in patients with advanced, estrogen receptor positive (ER+)/HER2-negative (HER2-) breast cancer. Resista ... Full text Cite

HOXB13 interaction with MEIS1 modifies proliferation and gene expression in prostate cancer.

Journal Article Prostate · March 2019 BACKGROUND: The recurrent p.Gly84Glu germline mutation (G84E) in HOXB13 is consistently associated with prostate cancer (PCa), although the mechanisms underlying such linkage remain elusive. The majority of the PCa-associated HOXB13 mutations identified ar ... Full text Link to item Cite

Targeting mutant estrogen receptors.

Journal Article Elife · January 16, 2019 A drug used in hormone replacement therapy can target estrogen receptors that have become resistant to breast cancer treatments. ... Full text Link to item Cite

27-Hydroxycholesterol, an Endogenous SERM, and Risk of Fracture in Postmenopausal Women: A Nested Case-Cohort Study in the Women's Health Initiative.

Journal Article J Bone Miner Res · January 2019 27-Hydroxycholesterol (27HC) is a purported, novel endogenous SERM. In animal models, 27HC has an anti-estrogen effect in bone, and 17β-estradiol mitigates this effect. 27HC in relation to fracture risk has not been investigated in humans. Depending on the ... Full text Link to item Cite

Abstract 5496: A predictive model for selective targeting of the Warburg effect through GAPDH inhibition with a natural product

Conference Cancer Research · July 1, 2018 AbstractCancer cells undergo numerous adaptive processes to sustain growth and survival. One notable mechanism is by rewiring metabolism, most prominently through a phenomenon known as the Warburg effect (WE ... Full text Cite

Thyroid hormone receptor and ERRα coordinately regulate mitochondrial fission, mitophagy, biogenesis, and function.

Journal Article Sci Signal · June 26, 2018 Thyroid hormone receptor β1 (THRB1) and estrogen-related receptor α (ESRRA; also known as ERRα) both play important roles in mitochondrial activity. To understand their potential interactions, we performed transcriptome and ChIP-seq analyses and found that ... Full text Link to item Cite

Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors.

Journal Article Nat Commun · April 26, 2018 Altered mitochondrial dynamics can broadly impact tumor cell physiology. Using genetic and pharmacological profiling of cancer cell lines and human tumors, we here establish that perturbations to the mitochondrial dynamics network also result in specific t ... Full text Link to item Cite

Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.

Journal Article J Med Chem · April 12, 2018 In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine thera ... Full text Link to item Cite

Validation of histone deacetylase 3 as a therapeutic target in castration-resistant prostate cancer.

Journal Article Prostate · March 2018 BACKGROUND: Whereas the androgen receptor (AR) signaling axis remains a therapeutic target in castration-resistant prostate cancer (CRPC), the emergence of AR mutations and splice variants as mechanisms underlying resistance to contemporary inhibitors of t ... Full text Link to item Cite

Neomorphic ERα Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery.

Journal Article Cancer Cell · February 12, 2018 In this issue of Cancer Cell, Jeselsohn et al. dissect the function of several of the most clinically important estrogen receptor alpha mutants associated with endocrine therapy resistance in breast cancer and demonstrate that they manifest disease-relevan ... Full text Open Access Link to item Cite

Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance.

Journal Article Commun Biol · 2018 The androgen receptor is a major driver of prostate cancer and inhibition of its transcriptional activity using competitive antagonists, such as enzalutamide remains a frontline therapy for prostate cancer management. However, the majority of patients even ... Full text Link to item Cite

The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells.

Journal Article Nat Commun · October 11, 2017 Obesity and elevated circulating cholesterol are risk factors for breast cancer recurrence, while the use of statins, cholesterol biosynthesis inhibitors widely used for treating hypercholesterolemia, is associated with improved disease-free survival. Here ... Full text Link to item Cite

A Predictive Model for Selective Targeting of the Warburg Effect through GAPDH Inhibition with a Natural Product.

Journal Article Cell Metab · October 3, 2017 Targeted cancer therapies that use genetics are successful, but principles for selectively targeting tumor metabolism that is also dependent on the environment remain unknown. We now show that differences in rate-controlling enzymes during the Warburg effe ... Full text Link to item Cite

DNA Sequence Constraints Define Functionally Active Steroid Nuclear Receptor Binding Sites in Chromatin.

Journal Article Endocrinology · October 2017 Gene regulatory programs are encoded in the sequence of the DNA. Since the completion of the Human Genome Project, millions of gene regulatory elements have been identified in the human genome. Understanding how each of those sites functionally contributes ... Full text Cite

Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling.

Journal Article Oncogene · July 27, 2017 Despite the advances in the diagnosis and treatment of breast cancer, breast cancers still cause significant mortality. For some patients, especially those with triple-negative breast cancer, current treatments continue to be limited and ineffective. There ... Full text Link to item Cite

Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling.

Journal Article Oncogene · July 27, 2017 This corrects the article DOI: 10.1038/onc.2016.394. ... Full text Link to item Cite

Impact of 27-hydroxylase (CYP27A1) and 27-hydroxycholesterol in breast cancer.

Journal Article Endocr Relat Cancer · July 2017 The impact of systemic 27-hydroxycholesterol (27HC) and intratumoral CYP27A1 expression on pathobiology and clinical response to statins in breast cancer needs clarification. 27HC is an oxysterol produced from cholesterol by the monooxygenase CYP27A1, whic ... Full text Link to item Cite

CDK4/6 Therapeutic Intervention and Viable Alternative to Taxanes in CRPC.

Journal Article Mol Cancer Res · June 2017 Resistance to second-generation androgen receptor (AR) antagonists and CYP17 inhibitors in patients with castration-resistant prostate cancer (CRPC) develops rapidly through reactivation of the androgen signaling axis and has been attributed to AR overexpr ... Full text Link to item Cite

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer.

Journal Article J Clin Invest · June 1, 2017 The clinical utility of inhibiting cytochrome P450 17A1 (CYP17), a cytochrome p450 enzyme that is required for the production of androgens, has been exemplified by the approval of abiraterone for the treatment of castration-resistant prostate cancer (CRPC) ... Full text Link to item Cite

Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer.

Journal Article J Med Chem · April 13, 2017 Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimizatio ... Full text Link to item Cite

CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer.

Journal Article Cancer Res · April 1, 2017 In this study, we used a bioinformatic approach to identify genes whose expression is dysregulated in human prostate cancers. One of the most dramatically downregulated genes identified encodes CYP27A1, an enzyme involved in regulating cellular cholesterol ... Full text Link to item Cite

MMTV-PyMT and Derived Met-1 Mouse Mammary Tumor Cells as Models for Studying the Role of the Androgen Receptor in Triple-Negative Breast Cancer Progression.

Journal Article Horm Cancer · April 2017 Triple-negative breast cancer (TNBC) has a faster rate of metastasis compared to other breast cancer subtypes, and no effective targeted therapies are currently FDA-approved. Recent data indicate that the androgen receptor (AR) promotes tumor survival and ... Full text Link to item Cite

Abstract P3-07-14: Targeting ERR-α regulated lactate metabolism eliminates drug-resistant breast cancer cells

Conference Cancer Research · February 15, 2017 AbstractNovel therapeutic strategies to eliminate chemo-resistant tumour cells responsible for the development of secondary lesions are essential in order to prevent breast cancer relapse. We have developed ... Full text Cite

Distinct Receptor Tyrosine Kinase Subsets Mediate Anti-HER2 Drug Resistance in Breast Cancer.

Journal Article J Biol Chem · January 13, 2017 Targeted inhibitors of the human epidermal growth factor receptor 2 (HER2), such as trastuzumab and lapatinib, are among the first examples of molecularly targeted cancer therapy and have proven largely effective for the treatment of HER2-positive breast c ... Full text Open Access Link to item Cite

Chemotherapy enriches for an invasive triple-negative breast tumor cell subpopulation expressing a precursor form of N-cadherin on the cell surface.

Journal Article Oncotarget · December 20, 2016 BACKGROUND: Although most triple-negative breast cancer (TNBC) patients initially respond to chemotherapy, residual tumor cells frequently persist and drive recurrent tumor growth. Previous studies from our laboratory and others' indicate that TNBC is hete ... Full text Link to item Cite

PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation.

Journal Article Sci Transl Med · December 14, 2016 Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that combined inhibition of B cell lymphoma-extra large (BCL-XL) a ... Full text Open Access Link to item Cite

CYP27A1/27HC/SREBP2 axis is a novel therapeutic target in prostate cancer

Conference European Journal of Cancer · December 2016 Full text Cite

Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer.

Journal Article Nat Chem Biol · October 2016 Clinical resistance to the second-generation antiandrogen enzalutamide in castration-resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights an unmet medical need for next-generation antagonists. We have i ... Full text Link to item Cite

MiR-148a functions to suppress metastasis and serves as a prognostic indicator in triple-negative breast cancer.

Journal Article Oncotarget · April 12, 2016 Triple-negative breast cancer (TNBC) presents a major challenge in the clinic due to its lack of reliable prognostic markers and targeted therapies. Accumulating evidence strongly supports the notion that microRNAs (miRNAs) are involved in tumorigenesis an ... Full text Link to item Cite

ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer.

Journal Article Cell Rep · April 12, 2016 Imaging studies in animals and in humans have indicated that the oxygenation and nutritional status of solid tumors is dynamic. Furthermore, the extremely low level of glucose within tumors, while reflecting its rapid uptake and metabolism, also suggests t ... Full text Link to item Cite

Abstract P3-14-04: Effects of the dual selective CYP17 lyase inhibitor and androgen receptor (AR) antagonist, VT-464, on AR+ and ER+ tumor models in vitro and in vivo

Conference Cancer Research · February 15, 2016 AbstractVT-464 is a lyase-selective inhibitor of the dual-activity CYP17A1 enzyme that is required for the synthesis of androgens and estrogens in the gonads, adrenals, and tumors. In addition to its role as ... Full text Cite

The Concise Guide to PHARMACOLOGY 2015/16: Overview.

Journal Article Br J Pharmacol · December 2015 The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), ... Full text Link to item Cite

Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer.

Journal Article Clin Cancer Res · November 15, 2015 PURPOSE: Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains first-line therapy for the management of estrogen receptor (ESR1)-positive breast cancer. However, ESR1 mutations or other ligand-independent ESR1 activation mechanisms limit th ... Full text Link to item Cite

Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader.

Journal Article Endocr Relat Cancer · October 2015 Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains a first-line treatment for estrogen receptor 1 (ESR1) positive breast cancer. However, tumor resistance limits the duration of response. The clinical efficacy of fulvestrant, a selective ... Full text Link to item Cite

Identification of a Novel Coregulator, SH3YL1, That Interacts With the Androgen Receptor N-Terminus.

Journal Article Mol Endocrinol · October 2015 Nuclear receptor (NR)-mediated transcriptional activity is a dynamic process that is regulated by the binding of ligands that induce distinct conformational changes in the NR. These structural alterations lead to the differential recruitment of coregulator ... Full text Link to item Cite

Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging.

Journal Article Angew Chem Int Ed Engl · August 10, 2015 Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR antagonist MDV3100/enzalutamide. Recent studies have shown ... Full text Link to item Cite

Abstract 2703: Overcoming Lapatinib resistance by the fatty acid synthase inhibitor HS-106

Conference Cancer Research · August 1, 2015 AbstractHuman epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that is overexpressed in about 20% of breast cancers and most often in the more aggressive inflammatory breast cancer (IB ... Full text Cite

Pregnancy and Smoothelin-like Protein 1 (SMTNL1) Deletion Promote the Switching of Skeletal Muscle to a Glycolytic Phenotype in Human and Mice.

Journal Article J Biol Chem · July 17, 2015 Pregnancy promotes physiological adaptations throughout the body, mediated by the female sex hormones progesterone and estrogen. Changes in the metabolic properties of skeletal muscle enable the female body to cope with the physiological challenges of preg ... Full text Link to item Cite

Oral Selective Estrogen Receptor Downregulators (SERDs), a Breakthrough Endocrine Therapy for Breast Cancer.

Journal Article J Med Chem · June 25, 2015 Drugs that inhibit estrogen receptor alpha (ERα) or that block the production of estrogens remain frontline interventions in the treatment and management of breast cancer at all stages. However, resistance to endocrine therapies, especially in the setting ... Full text Link to item Cite

Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer.

Journal Article Mol Oncol · June 2015 Cancer cells often have increased levels of reactive oxygen species (ROS); however, acquisition of redox adaptive mechanisms allows for evasion of ROS-mediated death. Inflammatory breast cancer (IBC) is a distinct, advanced BC subtype characterized by high ... Full text Link to item Cite

Direct effects of the selective CYP17 lyase (L) inhibitor, VT-464, on the androgen receptor (AR) and its oral activity in an F876L tumor mouse xenograft model.

Conference Journal of Clinical Oncology · March 1, 2015 263 Background: MDV3100 inhibits binding of androgens to AR and abiraterone is known to block androgen production through CYP17 inhibition; both are effective treatments for castration-resistant prostate cancer (CRPC, yet cross-r ... Full text Cite

Aryl hydrocarbon receptor knock-out exacerbates choroidal neovascularization via multiple pathogenic pathways.

Journal Article J Pathol · January 2015 The aryl hydrocarbon receptor (AhR) is a heterodimeric transcriptional regulator with pleiotropic functions in xenobiotic metabolism and detoxification, vascular development and cancer. Herein, we report a previously undescribed role for the AhR signalling ... Full text Link to item Cite

Systematic identification of signaling pathways with potential to confer anticancer drug resistance.

Journal Article Sci Signal · December 23, 2014 Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the pres ... Full text Link to item Cite

Delineation of a FOXA1/ERα/AGR2 regulatory loop that is dysregulated in endocrine therapy-resistant breast cancer.

Journal Article Mol Cancer Res · December 2014 UNLABELLED: Tamoxifen, a selective estrogen receptor (ER) modulator (SERM), remains a frontline clinical therapy for patients with ERα-positive breast cancer. However, the relatively rapid development of resistance to this drug in the metastatic setting re ... Full text Link to item Cite

The estrogen receptor as a mediator of the pathological actions of cholesterol in breast cancer.

Journal Article Climacteric · December 2014 Despite increased survivorship among patients, breast cancer remains the most common cancer among women and is the second leading cause of cancer death in women. The magnitude of this problem provides a strong impetus for new chemopreventative strategies a ... Full text Link to item Cite

Cholesterol and breast cancer pathophysiology.

Journal Article Trends Endocrinol Metab · December 2014 Cholesterol is a risk factor for breast cancer although the mechanisms by which this occurs are not well understood. One hypothesis is that dyslipidemia results in increased cholesterol content in cell membranes, thus impacting upon membrane fluidity and s ... Full text Link to item Cite

From empirical to mechanism-based discovery of clinically useful Selective Estrogen Receptor Modulators (SERMs).

Journal Article Steroids · November 2014 Our understanding of the molecular mechanisms underlying the pharmacological actions of estrogen receptor (ER) ligands has evolved considerably in recent years. Much of this knowledge has come from a detailed dissection of the mechanism(s) of action of the ... Full text Link to item Cite

Copper signaling axis as a target for prostate cancer therapeutics.

Journal Article Cancer Res · October 15, 2014 Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for pro ... Full text Open Access Link to item Cite

Abstract 3311: The cholesterol/ 27-hydroxycholesterol axis is a novel therapeutic target in castrate resistant prostate cancer

Conference Cancer Research · October 1, 2014 AbstractThe most recent estimates indicate that men have a seventeen percent chance of developing invasive prostate cancer (PCa) over their lifetime. This makes PCa the most commonly diagnosed malignancy amo ... Full text Cite

Abstract 4570: Role of ERRalpha in ovarian cancer

Conference Cancer Research · October 1, 2014 AbstractObjective. The estrogen receptor-related receptor-alpha (ERRα, encoded by ESRRA) has emerged as a key transcriptional regulator of mitochondrial function and has been implicated as a prognostic marke ... Full text Cite

Endocrine Society 2014 Laureate Awards.

Journal Article Horm Cancer · October 2014 Full text Link to item Cite

Obesity, cholesterol metabolism, and breast cancer pathogenesis.

Journal Article Cancer Res · September 15, 2014 Obesity and altered lipid metabolism are risk factors for breast cancer in pre- and post-menopausal women. These pathologic relationships have been attributed in part to the impact of cholesterol on the biophysical properties of cell membranes and to the i ... Full text Link to item Cite

Use of phage display to identify novel mineralocorticoid receptor-interacting proteins.

Journal Article Mol Endocrinol · September 2014 The mineralocorticoid receptor (MR) plays a central role in salt and water homeostasis via the kidney; however, inappropriate activation of the MR in the heart can lead to heart failure. A selective MR modulator that antagonizes MR signaling in the heart b ... Full text Link to item Cite

Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5α-dihydroprogesterone.

Journal Article Proc Natl Acad Sci U S A · March 4, 2014 One of the most widely accepted axioms of mammalian reproductive biology is that pregnancy requires the (sole) support of progesterone, acting in large measure through nuclear progesterone receptors (PRs) in uterine and cervical tissues, without which preg ... Full text Link to item Cite

ELF3 is a repressor of androgen receptor action in prostate cancer cells.

Journal Article Oncogene · February 13, 2014 The androgen receptor (AR) has a critical role in the development and progression of prostate cancer (PC) and is a major therapeutic target in this disease. The transcriptional activity of AR is modulated by the coregulators with which it interacts, and co ... Full text Link to item Cite

4,4'-Unsymmetrically substituted 3,3'-biphenyl alpha helical proteomimetics as potential coactivator binding inhibitors.

Journal Article Bioorg Med Chem · January 15, 2014 A series of unsymmetrically substituted biphenyl compounds was designed as alpha helical proteomimetics with the aim of inhibiting the binding of coactivator proteins to the nuclear hormone receptor coactivator binding domain. These compounds were synthesi ... Full text Link to item Cite

27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology.

Journal Article Science · November 29, 2013 Hypercholesterolemia is a risk factor for estrogen receptor (ER)-positive breast cancers and is associated with a decreased response of tumors to endocrine therapies. Here, we show that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol and ... Full text Link to item Cite

Aryl hydrocarbon receptor deficiency causes dysregulated cellular matrix metabolism and age-related macular degeneration-like pathology.

Journal Article Proc Natl Acad Sci U S A · October 22, 2013 The aryl hydrocarbon receptor (AhR) is a nuclear receptor that regulates xenobiotic metabolism and detoxification. Herein, we report a previously undescribed role for the AhR signaling pathway as an essential defense mechanism in the pathogenesis of early ... Full text Link to item Cite

Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease.

Journal Article Clin Cancer Res · May 1, 2013 PURPOSE: There is compelling evidence to suggest that drugs that function as pure estrogen receptor (ER-α) antagonists, or that downregulate the expression of ER-α, would have clinical use in the treatment of advanced tamoxifen- and aromatase-resistant bre ... Full text Link to item Cite

The molecular mechanisms underlying the pharmacological actions of estrogens, SERMs and oxysterols: implications for the treatment and prevention of osteoporosis.

Journal Article Bone · March 2013 Estrogen therapy and hormone therapy are effective options for the prevention and treatment of osteoporosis, although because of their significant side effect profile, long term use for these applications is not recommended. Whereas SERMs (Selective Estrog ... Full text Link to item Cite

Abstract PR3: The cholesterol metabolite 27-hydroxycholesterol increases breast cancer tumor growth and metastasis

Journal Article Cancer Research · February 1, 2013 AbstractBreast cancer remains the most common cancer and is the second leading cause of cancer death in women. The magnitude of this problem provides strong rationale for studies that may lead to the develop ... Full text Cite

Androgens promote prostate cancer cell growth through induction of autophagy.

Journal Article Mol Endocrinol · February 2013 Androgens regulate both the physiological development of the prostate and the pathology of prostatic diseases. However, the mechanisms by which androgens exert their regulatory activities on these processes are poorly understood. In this study, we have det ... Full text Link to item Cite

Regulation of Bone Cell Function by Estrogens

Journal Article · January 1, 2013 The biological actions of estrogens are manifest in cells expressing either of two genetically and functionally distinct estrogen receptors (ERs). Although generally considered reproductive hormones, estrogens are also key regulators of processes involved ... Full text Cite

Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes.

Journal Article J Clin Invest · January 2013 Cyclin D1b is a splice variant of the cell cycle regulator cyclin D1 and is known to harbor divergent and highly oncogenic functions in human cancer. While cyclin D1b is induced during disease progression in many cancer types, the mechanisms underlying cyc ... Full text Link to item Cite

Molecular pathways: the metabolic regulator estrogen-related receptor α as a therapeutic target in cancer.

Journal Article Clin Cancer Res · November 15, 2012 The estrogen-related receptor α (ERRα) is an orphan member of the nuclear receptor superfamily of transcription factors whose activity is regulated by the expression level and/or activity of its obligate coregulators, peroxisome proliferator-activated rece ... Full text Link to item Cite

3,3'-Disubstituted bipolar biphenyls as inhibitors of nuclear receptor coactivator binding.

Journal Article Bioorg Med Chem Lett · November 1, 2012 A series of bipolar biphenyl compounds was synthesized as proteomimetic analogs of the LXXLL penta-peptide motif responsible for the binding of coactivator proteins to the nuclear hormone receptor coactivator binding domain. These compounds were subjected ... Full text Link to item Cite

Lysine-specific histone demethylase 1 inhibitors control breast cancer proliferation in ERα-dependent and -independent manners.

Journal Article ACS Chem Biol · July 20, 2012 Lysine specific demethylase 1 (LSD1, also known as KDM1) is a histone modifying enzyme that regulates the expression of many genes important in cancer progression and proliferation. It is present in various transcriptional complexes including those contain ... Full text Link to item Cite

Research resource: Transcriptional profiling in a cellular model of breast cancer reveals functional and mechanistic differences between clinically relevant SERM and between SERM/estrogen complexes.

Journal Article Mol Endocrinol · July 2012 Exploitation of the relationship between estrogen receptor (ER) structure and activity has led to the development of 1) selective ER modulators (SERM), compounds whose relative agonist/antagonist activities differ between target tissues; 2) selective ER de ... Full text Link to item Cite

The oxysterol, 27-hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver X receptors.

Journal Article Endocrinology · December 2011 Osteoporosis and age-related bone loss are important public health concerns. Therefore, there is a high level of interest in the development of medical interventions and lifestyle changes that reduce the incidence of osteoporosis and age-related bone loss. ... Full text Link to item Cite

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation.

Journal Article Proc Natl Acad Sci U S A · November 8, 2011 Stimulation of resting CD4(+) T lymphocytes leads to rapid proliferation and differentiation into effector (Teff) or inducible regulatory (Treg) subsets with specific functions to promote or suppress immunity. Importantly, Teff and Treg use distinct metabo ... Full text Link to item Cite

The metabolic regulator ERRα, a downstream target of HER2/IGF-1R, as a therapeutic target in breast cancer.

Journal Article Cancer Cell · October 18, 2011 A genomic signature designed to assess the activity of the estrogen-related receptor alpha (ERRα) was used to profile more than 800 breast tumors, revealing a shorter disease-free survival in patients with tumors exhibiting elevated receptor activity. Impo ... Full text Link to item Cite

Smoothelin-like 1 protein is a bifunctional regulator of the progesterone receptor during pregnancy.

Journal Article J Biol Chem · September 9, 2011 During pregnancy, uterine smooth muscle (USM) coordinately adapts its contractile phenotype in order to accommodate the developing fetus and then prepare for delivery. Herein we show that SMTNL1 plays a major role in pregnancy to promote adaptive responses ... Full text Link to item Cite

The turnover of estrogen receptor α by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy.

Journal Article Biochem Pharmacol · July 15, 2011 It has become apparent of late that even in tamoxifen and/or aromatase resistant breast cancers, ERα remains a bona fide therapeutic target. Not surprisingly, therefore, there has been considerable interest in developing Selective ER Degraders (SERDs), com ... Full text Link to item Cite

Research resource: nuclear receptor atlas of human retinal pigment epithelial cells: potential relevance to age-related macular degeneration.

Journal Article Mol Endocrinol · February 2011 Retinal pigment epithelial (RPE) cells play a vital role in retinal physiology by forming the outer blood-retina barrier and supporting photoreceptor function. Retinopathies including age-related macular degeneration (AMD) involve physiological and patholo ... Full text Link to item Cite

CaM kinase kinase beta-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells.

Journal Article Cancer Res · January 15, 2011 While patients with advanced prostate cancer initially respond favorably to androgen ablation therapy, most experience a relapse of the disease within 1-2 years. Although hormone-refractory disease is unresponsive to androgen-deprivation, androgen receptor ... Full text Link to item Cite

Identification of ligand-selective peptide antagonists of the mineralocorticoid receptor using phage display.

Journal Article Mol Endocrinol · January 2011 The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily. Pathological activation of the MR causes cardiac fibrosis and heart failure, but clinical use of MR antagonists is limited by the renal side effect of hyperkalemia. The gl ... Full text Link to item Cite

Mechanisms of progesterone receptor inhibition of inflammatory responses in cellular models of breast cancer.

Journal Article Mol Endocrinol · December 2010 Both pro- and antimitogenic activities have been ascribed to progesterone receptor (PR) agonists and antagonists in breast cancer cells; however, the transcriptional responses that underlie these paradoxical functions are not apparent. Using nontransformed ... Full text Link to item Cite

The molecular mechanisms underlying the pharmacological actions of ER modulators: implications for new drug discovery in breast cancer.

Journal Article Curr Opin Pharmacol · December 2010 Our understanding of the molecular mechanisms underlying the pharmacological actions of estrogen receptor (ER) ligands has evolved considerably in recent years. Much of this knowledge has come from a detailed dissection of the mechanism(s) of action of the ... Full text Link to item Cite

WNT11 expression is induced by estrogen-related receptor alpha and beta-catenin and acts in an autocrine manner to increase cancer cell migration.

Journal Article Cancer Res · November 15, 2010 Elevated expression of the orphan nuclear receptor estrogen-related receptor α (ERRα) has been associated with a negative outcome in several cancers, although the mechanism(s) by which this receptor influences the pathophysiology of this disease and how it ... Full text Link to item Cite

An interdomain interaction of the androgen receptor is required for its aggregation and toxicity in spinal and bulbar muscular atrophy.

Journal Article J Biol Chem · November 12, 2010 Polyglutamine expansion within the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA) and is associated with misfolded and aggregated species of the mutant AR. We showed previously that nuclear localization of the mutant AR was necessa ... Full text Link to item Cite

The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis.

Journal Article Endocrinology · August 2010 Osteoporosis is an important clinical problem, affecting more than 50% of people over age 50 yr. Estrogen signaling is critical for maintaining proper bone density, and the identification of an endogenous selective estrogen receptor (ER) modulator, 27-hydr ... Full text Link to item Cite

Expression, purification and primary crystallographic study of human androgen receptor in complex with DNA and coactivator motifs.

Journal Article Protein Expr Purif · May 2010 The androgen receptor (AR) is a DNA-binding and hormone-activated transcription factor that plays critical roles in the development and progression of prostate cancer. The transcriptional function of AR is modulated by intermolecular interactions with DNA ... Full text Link to item Cite

Multimodal regulation of E2F1 gene expression by progestins.

Journal Article Mol Cell Biol · April 2010 An analysis of mRNA expression in T47D breast cancer cells treated with the synthetic progestin R5020 revealed a subset of progesterone receptor (PR) target genes that are enriched for E2F binding sites. Following up on this observation, we determined that ... Full text Link to item Cite

Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity.

Journal Article Stem Cells · March 31, 2010 Hematopoietic stem cells (HSCs) are enriched for aldehyde dehydrogenase (ALDH) activity and ALDH is a selectable marker for human HSCs. However, the function of ALDH in HSC biology is not well understood. We sought to determine the function of ALDH in regu ... Full text Link to item Cite

ERRgamma regulates cardiac, gastric, and renal potassium homeostasis.

Journal Article Mol Endocrinol · February 2010 Energy production by oxidative metabolism in kidney, stomach, and heart, is primarily expended in establishing ion gradients to drive renal electrolyte homeostasis, gastric acid secretion, and cardiac muscle contraction, respectively. In addition to orches ... Full text Link to item Cite

Activation of the aryl-hydrocarbon receptor inhibits invasive and metastatic features of human breast cancer cells and promotes breast cancer cell differentiation.

Journal Article Mol Endocrinol · February 2010 The current statistics associated with breast cancer continue to show a relatively high recurrence rate together with a poor survival for aggressive metastatic disease. These findings reflect, in part, the pharmaceutical intractability of processes involve ... Full text Link to item Cite

Minireview: Nuclear receptors, hematopoiesis, and stem cells.

Journal Article Mol Endocrinol · January 2010 Nuclear receptors (NRs) regulate a panoply of biological processes, including the function and development of cells within the hematopoietic and immune system, such as erythrocytes, monocytes, and lymphocytes. Significantly less is known regarding the func ... Full text Link to item Cite

Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators.

Journal Article Mol Endocrinol · January 2010 Selective estrogen receptor modulators (SERMs), such as tamoxifen (TAM), have been used extensively for the treatment and prevention of breast cancer and other pathologies associated with aberrant estrogen receptor (ER) signaling. These compounds exhibit c ... Full text Link to item Cite

The homeodomain protein HOXB13 regulates the cellular response to androgens.

Journal Article Mol Cell · November 13, 2009 HOXB13 is a member of the homeodomain family of sequence-specific transcription factors and, together with the androgen receptor (AR), plays a critical role in the normal development of the prostate gland. We demonstrate here that, in prostate cancer cells ... Full text Link to item Cite

Induction of Kruppel-like factor 5 expression by androgens results in increased CXCR4-dependent migration of prostate cancer cells in vitro.

Journal Article Mol Endocrinol · September 2009 Advanced prostate cancers preferentially metastasize to bone, suggesting that this tissue produces factors that provide a suitable microenvironment for prostate cancer cells. Recently, it has become clear that even in antiandrogen-resistant cancers, the an ... Full text Link to item Cite

Fasting-induced hepatic production of DHEA is regulated by PGC-1alpha, ERRalpha, and HNF4alpha.

Journal Article Mol Endocrinol · August 2009 The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha is involved in the coordinate induction of changes in gene expression in the liver that enable a homeostatic response to alterations in metabolic stat ... Full text Link to item Cite

Inhibition of prostate cancer cell growth by second-site androgen receptor antagonists.

Journal Article Proc Natl Acad Sci U S A · July 21, 2009 The impact of ligand binding on nuclear receptor (NR) structure and the ability of target cells to distinguish between different receptor-ligand complexes are key determinants of the pharmacological activity of NR ligands. However, until relatively recentl ... Full text Link to item Cite

Differential presentation of protein interaction surfaces on the androgen receptor defines the pharmacological actions of bound ligands.

Journal Article Chem Biol · April 24, 2009 The pharmacological activity of different nuclear receptor ligands is reflected by their impact on receptor structure. Thus, we asked whether differential presentation of protein-protein interaction surfaces on the androgen receptor (AR), a surrogate assay ... Full text Link to item Cite

Purification and characterization of recombinant human mineralocorticoid receptor.

Journal Article Mol Cell Endocrinol · April 10, 2009 The mineralocorticoid receptor (MR) plays a critical role in the maintenance of electrolyte homeostasis and blood pressure via direct effects on the distal nephron and the cardiovascular system. The MR also has an important role in the pathology of cardiov ... Full text Link to item Cite

Estrogen-related receptor alpha induces the expression of vascular endothelial growth factor in breast cancer cells.

Journal Article J Steroid Biochem Mol Biol · March 2009 Estrogen-related receptor alpha (ERRalpha) is an orphan member of the nuclear receptor family of transcription factors. In addition to its function as a metabolic regulator, ERRalpha has been implicated in the growth and progression of several malignancies ... Full text Link to item Cite

Glucose metabolism as a target of histone deacetylase inhibitors.

Journal Article Mol Endocrinol · March 2009 The therapeutic efficacy of histone deacetylase inhibitors (HDACI) is generally attributed to their ability to alter gene expression secondary to their effects on the acetylation status of transcription factors and histones. However, because HDACIs exhibit ... Full text Link to item Cite

Pharmacological manipulation of the RAR/RXR signaling pathway maintains the repopulating capacity of hematopoietic stem cells in culture.

Journal Article Mol Endocrinol · February 2009 The retinoid X receptor (RXR) contributes to the regulation of diverse biological pathways via its role as a heterodimeric partner of several nuclear receptors. However, RXR has no established role in the regulation of hematopoietic stem cell (HSC) fate. I ... Full text Link to item Cite

Characterization of antiestrogenic activity of the Chinese herb, prunella vulgaris, using in vitro and in vivo (Mouse Xenograft) models.

Journal Article Biol Reprod · February 2009 Prunella vulgaris (PV), a commonly used Chinese herb, also known as Self-heal, has a wide range of reported medicinal activities. By screening multiple herbs using the endometrial cancer cell line, ECC-1, and an alkaline phosphatase detection assay, we fou ... Full text Link to item Cite

Estrogen-related receptor alpha is critical for the growth of estrogen receptor-negative breast cancer.

Journal Article Cancer Res · November 1, 2008 Expression of estrogen-related receptor alpha (ERRalpha) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of this orphan nuclear receptor in tumor growth and progression, however, is yet to ... Full text Link to item Cite

Definition of Functionally Important Mechanistic Differences among Selective Estrogen Receptor Modulators

Conference MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY · November 1, 2008 Link to item Cite

27-Hydroxycholesterol: a potential endogenous regulator of estrogen receptor signaling.

Journal Article Trends Pharmacol Sci · October 2008 The selective estrogen receptor modulators (SERMs) are synthetic pharmaceuticals, the relative agonist and antagonist activities of which are not equivalent in all cells. Their discovery has raised the possibility that endogenous small molecules might exis ... Full text Link to item Cite

Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic.

Journal Article Cancer Res · September 15, 2008 Androgens, through their actions on the androgen receptor (AR), are required for the development of the prostate and contribute to the pathologic growth dysregulation observed in prostate cancers. Consequently, androgen ablation has become an essential com ... Full text Link to item Cite

Differential effects of prostate cancer therapeutics on neuroendocrine transdifferentiation.

Journal Article Mol Cancer Ther · March 2008 Androgen ablation therapy is widely used for the treatment of advanced prostate cancer. However, the effectiveness of this intervention strategy is generally short-lived as the disease ultimately progresses to a hormone-refractory state. In recent years, i ... Full text Link to item Cite

Nuclear receptor cofactor interactions as targets for new drug discovery

Chapter · January 1, 2008 The classical models of nuclear receptor pharmacology held that agonists functioned by binding to their cognate receptors facilitating their conversion from an inactive form to one that was capable of activating transcription. By extrapolation, it was cons ... Full text Cite

The commercialism of academic research

Journal Article Nature Medicine · January 1, 2008 Full text Cite

27-hydroxycholesterol is an endogenous selective estrogen receptor modulator.

Journal Article Mol Endocrinol · January 2008 Selective estrogen receptor (ER) modulators (SERMs) are ER ligands whose relative agonist/antagonist activities vary in a cell- and promoter-dependent manner. The molecular basis underlying this selectivity can be attributed to the ability of these ligands ... Full text Link to item Cite

On the intractability of estrogen-related receptor alpha as a target for activation by small molecules.

Journal Article J Med Chem · December 27, 2007 The estrogen-related receptor alpha (ERRalpha) is a potential target for activation in the treatment of metabolic disease. To date, no small-molecule agonists of ERRalpha have been identified despite several high-throughput screening campaigns. We describe ... Full text Link to item Cite

Molecular pharmacology of estrogen and progesterone receptors

Journal Article · December 1, 2007 This chapter provides an update on the mechanisms of action of estrogen and progesterone. Particularly important concepts include nongenomic effects, receptor isoforms that affect agonist/antagonist actions, and the role of coactivators and corepressors in ... Full text Cite

The nuclear receptor-coactivator interaction surface as a target for peptide antagonists of the peroxisome proliferator-activated receptors.

Journal Article Mol Endocrinol · October 2007 The peroxisome proliferator-activated receptors (PPARalpha, PPARdelta, and PPARgamma) constitute a family of nuclear receptors that regulates metabolic processes involved in lipid and glucose homeostasis. Although generally considered to function as ligand ... Full text Link to item Cite

Definition of functionally important mechanistic differences among selective estrogen receptor down-regulators.

Journal Article Cancer Res · October 1, 2007 One subclass of antiestrogens, the selective estrogen receptor down-regulators (SERDs), have received considerable attention of late as they competitively inhibit estrogen binding and induce a rapid, proteasome-dependent degradation of the receptor. Contai ... Full text Link to item Cite

The molecular mechanisms underlying the proinflammatory actions of thiazolidinediones in human macrophages.

Journal Article Mol Endocrinol · August 2007 It is hypothesized that the antiinflammatory actions of peroxisome proliferator-activated receptors (PPARs) may explain the protective effect of these receptors in diabetes, atherosclerosis, cancer, and other inflammatory diseases. However, emerging eviden ... Full text Link to item Cite

The vitamin D receptor interacts preferentially with DRIP205-like LxxLL motifs.

Journal Article Arch Biochem Biophys · April 15, 2007 The vitamin D receptor (VDR) mediates the biological actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) through its capacity to recruit coregulatory proteins. This interaction is mediated via a coregulatory LxxLL motif. We screened a combinatorial (x)7LxxLL ... Full text Link to item Cite

Structural insights into corepressor recognition by antagonist-bound estrogen receptors.

Journal Article J Biol Chem · April 6, 2007 Direct recruitment of transcriptional corepressors to estrogen receptors (ER) is thought to contribute to the tissue-specific effects of clinically important ER antagonists. Here, we present the crystal structures of two affinity-selected peptides in compl ... Full text Link to item Cite

Molecular Pharmacology of Estrogen and Progesterone Receptors

Chapter · January 1, 2007 This chapter provides an update on the mechanisms of action of estrogen and progesterone. Particularly important concepts include nongenomic effects, receptor isoforms that affect agonist/antagonist actions, and the role of coactivators and corepressors in ... Full text Cite

Definition of the molecular basis for estrogen receptor-related receptor-alpha-cofactor interactions.

Journal Article Mol Endocrinol · January 2007 Estrogen receptor-related receptor-alpha (ERRalpha) is an orphan nuclear receptor that does not appear to require a classical small molecule ligand to facilitate its interaction with coactivators and/or hormone response elements within target genes. Instea ... Full text Link to item Cite

Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression.

Journal Article J Biol Chem · December 29, 2006 The pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the oxidation of glucose to acetyl-CoA. Phosphorylation of PDC by the pyruvate dehydrogenase kinases (PDK2 and PDK ... Full text Link to item Cite

Receptor-selective coactivators as tools to define the biology of specific receptor-coactivator pairs.

Journal Article Mol Cell · December 8, 2006 In the absence of specific high-affinity agonists and antagonists, it has been difficult to define the target genes and biological responses attributable to many of the orphan nuclear receptors (ONRs). Indeed, it appears that many members of this receptor ... Full text Link to item Cite

Estrogen-related receptor alpha as a therapeutic target in cancer.

Journal Article Endocr Relat Cancer · December 2006 The orphan receptor estrogen-related receptor alpha (ERR alpha) is a member of the nuclear receptor superfamily of ligand-regulated transcription factors. This protein is structurally most related to the canonical estrogen receptor and has been shown to mo ... Full text Link to item Cite

Research resource articles - A new feature for Molecular Endocrinology

Journal Article Molecular Endocrinology · August 31, 2006 Full text Cite

Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells.

Journal Article Proc Natl Acad Sci U S A · August 1, 2006 Aldehyde dehydrogenase (ALDH) is an enzyme that is expressed in the liver and is required for the conversion of retinol (vitamin A) to retinoic acids. ALDH is also highly enriched in hematopoietic stem cells (HSCs) and is considered a selectable marker of ... Full text Link to item Cite

Human PXR forms a tryptophan zipper-mediated homodimer.

Journal Article Biochemistry · July 18, 2006 The human nuclear receptor pregnane X receptor (PXR) responds to a wide variety of potentially harmful chemicals and coordinates the expression of genes central to xenobiotic and endobiotic metabolism. Structural studies reveal that the PXR ligand binding ... Full text Link to item Cite

Linking ligand-induced alterations in androgen receptor structure to differential gene expression: a first step in the rational design of selective androgen receptor modulators.

Journal Article Mol Endocrinol · June 2006 We have previously identified a family of novel androgen receptor (AR) ligands that, upon binding, enable AR to adopt structures distinct from that observed in the presence of canonical agonists. In this report, we describe the use of these compounds to es ... Full text Link to item Cite

Estrogen-related receptor α as a therapeutic target

Journal Article Drugs of the Future · May 1, 2006 The utility of nuclear receptors (NRs) as targets for drug discovery is well recognized. Growing evidence suggests that ERRα, an orphan NR whose physiological and pathological roles remain under investigation, may have utility in the treatment of various c ... Full text Cite

SARMS, SERMS, SGRM

Conference OSTEOPOROSIS INTERNATIONAL · May 1, 2006 Link to item Cite

Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRgamma.

Journal Article Bioorg Med Chem Lett · February 15, 2006 The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor gamma and the classical estrogen receptor alpha demonstrate that analogs bearing hydroxy ... Full text Link to item Cite

Crystal structure of the human LRH-1 DBD-DNA complex reveals Ftz-F1 domain positioning is required for receptor activity.

Journal Article J Mol Biol · December 16, 2005 The DNA-binding and ligand-binding functions of nuclear receptors are localized to independent domains separated by a flexible hinge. The DNA-binding domain (DBD) of the human liver receptor homologue-1 (hLRH-1), which controls genes central to development ... Full text Link to item Cite

Coactivation of liver receptor homologue-1 by peroxisome proliferator-activated receptor gamma coactivator-1alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy.

Journal Article Cancer Res · December 15, 2005 Aromatase inhibitors target the production of estrogen in breast adipose tissue, but in doing so, also decrease estrogen formation in bone and other sites, giving rise to deleterious side effects, such as bone loss and arthralgia. Thus, it would be clinica ... Full text Link to item Cite

Coregulators in nuclear estrogen receptor action: from concept to therapeutic targeting.

Journal Article Mol Interv · December 2005 Estrogens are key regulators of growth, differentiation, and the physiological functions of a wide range of target tissues, including the male and female reproductive tracts, breast, and skeletal, nervous, cardiovascular, digestive and immune systems. The ... Full text Link to item Cite

Development of peptide antagonists for the androgen receptor using combinatorial peptide phage display.

Journal Article Mol Endocrinol · October 2005 Under the auspices of the Nuclear Receptor Signaling Atlas (NURSA), we have undertaken to evaluate the feasibility of targeting nuclear receptor-coactivator surfaces for new drug discovery. The underlying objective of this approach is to provide the resear ... Full text Link to item Cite

Structural basis for an unexpected mode of SERM-mediated ER antagonism.

Journal Article Mol Cell · May 13, 2005 Tamoxifen is effective for the prevention and treatment of estrogen-dependent breast cancers, but is associated with an increased incidence of endometrial tumors. We report the crystal structure of the estrogen receptor alpha (ERalpha) ligand binding domai ... Full text Link to item Cite

Identification and structure-activity relationship of phenolic acyl hydrazones as selective agonists for the estrogen-related orphan nuclear receptors ERRbeta and ERRgamma.

Journal Article J Med Chem · May 5, 2005 The first small molecule agonists of the estrogen-related receptors have been identified. GSK4716 (3) and GSK9089 (4) show binding to ERRgamma with remarkable selectivity over the classical estrogen receptors. Notably, in cell-based reporter assays, 3 mimi ... Full text Link to item Cite

Androgen receptor-cofactor interactions as targets for new drug discovery.

Journal Article Trends Pharmacol Sci · May 2005 Cofactor recruitment is a crucial regulatory step in nuclear receptor signal transduction. Given the obligate nature of interactions between cofactors and these receptors for transcriptional activity, it is likely that drugs that target coactivator interac ... Full text Link to item Cite

Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP.

Journal Article Nat Struct Mol Biol · April 2005 The human nuclear receptor liver receptor homolog 1 (hLRH-1) plays an important role in the development of breast carcinomas. This orphan receptor is efficiently downregulated by the unusual co-repressor SHP and has been thought to be ligand-independent. W ... Full text Link to item Cite

Characterization of transcriptional activation and DNA-binding functions in the hinge region of the vitamin D receptor.

Journal Article Biochemistry · February 22, 2005 The vitamin D receptor (VDR) is a ligand-responsive transcription factor that forms active, heterodimeric complexes with the 9-cis retinoic acid receptor (RXR) on vitamin D response elements (VDREs). Both proteins consist of an N-terminal DNA-binding domai ... Full text Link to item Cite

Gene expression profiling of breast cancer in relation to estrogen receptor status and estrogen-metabolizing enzymes: clinical implications.

Journal Article Clin Cancer Res · January 15, 2005 Interactions between luminal epithelial cells and their surrounding microenvironment govern the normal development and function of the mammary gland. Estradiol plays a key role in abnormal intracellular signaling, which contributes to the development and p ... Link to item Cite

Tamoxifen versus aromatase inhibitors for breast cancer prevention.

Journal Article Clin Cancer Res · January 15, 2005 Long-term exposure to estradiol is associated with an increased risk of breast cancer, but the mechanisms responsible are not firmly established. The prevailing theory postulates that estrogens increase the rate of cell proliferation by stimulating estroge ... Link to item Cite

Proceedings of the Fourth International Conference on Recent Advances and Future Directions in Endocrine Manipulation of Breast Cancer: Conference summary statement

Journal Article Clinical Cancer Research · January 15, 2005 The Fourth International Conference on Recent Advances and Future Directions in Endocrine Manipulation of Breast Cancer, co-chaired by Steven Come, MD, and Aman Buzdar, MD, was held in Cambridge, MA, July 21-22, 2004. The conference was organized with the ... Cite

Estrogen, estrogen plus progestin therapy, and risk of breast cancer.

Journal Article Clin Cancer Res · January 15, 2005 Epidemiologic evidence relating use of postmenopausal hormones to risk of breast cancer by nature relies on trends in prescribing practices. Data on the adverse effect of combination estrogen plus progestin used for long durations has only become available ... Link to item Cite

The molecular pharmacology of estrogen receptor modulators: Implications for the treatment of breast cancer

Journal Article Clinical Cancer Research · January 15, 2005 In addition to physiologic activities in the reproductive, skeletal, and central nervous systems, estrogens have been shown to play important roles in the aberrant cell proliferation observed in breast and reproductive tract cancers. Not surprisingly, phar ... Cite

The molecular pharmacology of estrogen receptor modulators: implications for the treatment of breast cancer.

Journal Article Clin Cancer Res · January 15, 2005 In addition to physiologic activities in the reproductive, skeletal, and central nervous systems, estrogens have been shown to play important roles in the aberrant cell proliferation observed in breast and reproductive tract cancers. Not surprisingly, phar ... Link to item Cite

Single-step purification of full-length human androgen receptor.

Journal Article Nucl Recept Signal · 2005 The full-length human androgen receptor with an N-terminal biotin acceptor peptide tag was overexpressed in Spodoptera frugiperda cells in the presence of 1 microM dihydrotestosterone. Site-specific biotinylation of BAP was achieved in vivo by co-expressio ... Full text Link to item Cite

The molecular determinants of estrogen receptor pharmacology.

Journal Article Maturitas · August 30, 2004 The classical models of steroid receptor pharmacology held that agonists functioned by binding to their cognate receptors, facilitating their conversion from an inactive form to one that was capable of activating transcription. By extrapolation, it was bel ... Full text Link to item Cite

Coactivator AIB1 links estrogen receptor transcriptional activity and stability.

Journal Article Proc Natl Acad Sci U S A · August 10, 2004 Agonist-mediated degradation of estrogen receptor alpha (ERalpha) has been associated with its transcriptional activity. However, the mechanism by which ERalpha is targeted for degradation and whether there is a direct functional link between ERalpha stabi ... Full text Link to item Cite

Hormone therapy: physiological complexity belies therapeutic simplicity.

Journal Article Science · May 28, 2004 The results of the Women's Health Initiative, a study anticipated to provide definitive answers about health benefits and risks of postmenopausal hormone therapy, have generated debate and confusion among clinicians, researchers, and the lay public. The ov ... Full text Link to item Cite

Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition.

Journal Article Proc Natl Acad Sci U S A · May 4, 2004 In this study, we demonstrate that the pervasive xenobiotic methoxyacetic acid and the commonly prescribed anticonvulsant valproic acid, both short-chain fatty acids (SCFAs), dramatically increase cellular sensitivity to estrogens, progestins, and other nu ... Full text Link to item Cite

Selective LXXLL peptides antagonize transcriptional activation by the retinoid-related orphan receptor RORgamma.

Journal Article Biochem Biophys Res Commun · March 19, 2004 The retinoid-related orphan receptor gamma (RORgamma) has been shown to function as a positive regulator of transcription in many cell lines. Transcriptional activation by nuclear receptors involves recruitment of co-activators that interact with receptors ... Full text Link to item Cite

The jensen symposium; a tribute to a pioneer in the field of nuclear receptor biology.

Journal Article Mol Cell · February 27, 2004 The Jensen Symposium was held at the University of Cincinnati in December 2003 to honor the pioneering contributions of Dr. Elwood Jensen to the field of nuclear hormone action. Those in attendance were treated to an outstanding scientific program that ser ... Full text Link to item Cite

Increased expression of estrogen receptor beta in pachytene spermatocytes after short-term methoxyacetic acid administration.

Journal Article J Androl · 2004 Degeneration of primary spermatocytes by apoptosis occurs during normal spermatogenesis, as well as in several pathological conditions, including exposure to specific testicular toxicants. The mechanisms that regulate the death and survival of primary sper ... Full text Link to item Cite

Pharmacological uncoupling of androgen receptor-mediated prostate cancer cell proliferation and prostate-specific antigen secretion.

Journal Article Cancer Res · November 15, 2003 The androgen receptor (AR), a member of the nuclear receptor family, is a ligand-inducible transcription factor. In the prostate gland, androgens regulate the transcription of several genes that ultimately result in cell growth and differentiation. With a ... Link to item Cite

Expression of functional estrogen receptor beta in locus coeruleus-derived Cath.a cells.

Journal Article Endocrinology · July 2003 Estrogen may have an important role in the brain beyond the development and regulation of reproductive function. Gender differences in the incidence of depression suggest that regulation of mood represents one such action. The locus coeruleus, a brain stem ... Full text Link to item Cite

Synthetic LXXLL peptide antagonize 1,25-dihydroxyvitamin D3-dependent transcription.

Journal Article J Cell Biochem · February 1, 2003 The vitamin D receptor (VDR) is known to mediate the biological actions of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) through its ability to regulate cellular programs of gene expression. We identified VDR- and retinoid X receptor (RXR)-interacting LXXLL ... Full text Link to item Cite

Function and mode of action of nuclear receptors: Estrogen, progesterone, and vitamin D

Journal Article Pure and Applied Chemistry · January 1, 2003 Estrogens and progestins play important roles in regulating growth and differentiation of a wide range of cell types, in both reproductive and nonreproductive tissues. Not surprisingly, therefore, endocrine active substances that mimic the actions of these ... Full text Cite

The impact of the women's health initiative on the search for improved treatments for the conditions associated with long-term oestrogen deprivation

Journal Article Journal of the British Menopause Society · January 1, 2003 Publication of the preliminary findings from the combination (oestrogen and progestogen) hormone therapy (HT) arm of the Women's Health Initiative (WHI) on the heels of the Heart and Estrogen/progestin Replacement Study (HERS) sent the field of menopausal ... Full text Cite

Inhibition of 1,25-dihydroxyvitamin D3-dependent transcription by synthetic LXXLL peptide antagonists that target the activation domains of the vitamin D and retinoid X receptors.

Journal Article J Bone Miner Res · December 2002 The vitamin D receptor (VDR) is known to mediate the biological actions of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] through its ability to regulate cellular programs of gene expression. Although RXR appears to participate as a heterodimeric partner with the ... Full text Link to item Cite

Problems for risk assessment of endocrine-active estrogenic compounds.

Journal Article Environ Health Perspect · December 2002 Estrogenic industrial compounds such as bisphenol A (BPA) and nonylphenol typically bind estrogen receptor (ER) alpha and ERBeta and induce transactivation of estrogen-responsive genes/reporter genes, but their potencies are usually greater than or equal t ... Full text Link to item Cite

Identification of a negative regulatory surface within estrogen receptor alpha provides evidence in support of a role for corepressors in regulating cellular responses to agonists and antagonists.

Journal Article Mol Endocrinol · August 2002 Several lines of evidence have indicated that the estrogen receptor (ER) can recruit the corepressors, nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid receptors (SMRT), to target genes in the presence of tamoxifen, sugges ... Full text Link to item Cite

Identification and characterization of novel estrogen receptor-beta-sparing antiprogestins.

Journal Article Endocrinology · August 2002 The steroid hormones estrogen and progesterone together regulate the development and maintenance of the female reproductive system. The actions of these two hormones are mediated by their respective nuclear receptors located within overlapping cell populat ... Full text Link to item Cite

Elucidation of the molecular mechanism of action of selective estrogen receptor modulators.

Journal Article Am J Cardiol · July 3, 2002 The term selective estrogen receptor modulator (SERM) describes a group of pharmaceuticals that manifest estrogen receptor (ER) agonist activity in some tissues but opposes estrogen action in others. Although the name describing this class of drugs is new, ... Full text Link to item Cite

Direct interactions between corepressors and coactivators permit the integration of nuclear receptor-mediated repression and activation.

Journal Article Mol Endocrinol · July 2002 The unliganded thyroid hormone receptor beta (TRbeta) represses the basal transcriptional activity of target genes, in part through interactions with the nuclear receptor corepressor (N-CoR). In this study we have identified a rather unexpected interaction ... Full text Link to item Cite

The transcription factor B-Myb is maintained in an inhibited state in target cells through its interaction with the nuclear corepressors N-CoR and SMRT.

Journal Article Mol Cell Biol · June 2002 The B-Myb transcription factor has been implicated in coordinating the expression of genes involved in cell cycle regulation. Although it is expressed in a ubiquitous manner, its transcriptional activity is repressed until the G(1)-S phase of the cell cycl ... Full text Link to item Cite

Connections and regulation of the human estrogen receptor.

Journal Article Science · May 31, 2002 Estrogen regulates a plethora of functionally dissimilar processes in a broad range of tissues. Recent progress in the study of the molecular mechanism of action of estrogen(s) has revealed why different cells can respond to the same hormone in a different ... Full text Link to item Cite

Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein.

Journal Article Circulation · April 23, 2002 BACKGROUND: The estrogen receptor-alpha (ER-alpha) IVS1-401 polymorphism identifies a group of women (approximately 20%) who have augmented effects of hormone replacement therapy (HRT) on levels of HDL cholesterol. This study sought to determine if this au ... Full text Link to item Cite

Evaluation of ligand-dependent changes in AR structure using peptide probes.

Journal Article Mol Endocrinol · April 2002 Mutations in the AR are frequently found in relapsed prostate cancers, some of which permit antiandrogens as well as nonandrogenic compounds to function as androgens. However, the molecular mechanism(s) by which these mutations enable this aberrant AR phar ... Full text Link to item Cite

A negative coregulator for the human ER.

Journal Article Mol Endocrinol · March 2002 ERalpha is a ligand-activated transcription factor and a key regulator of the processes involved in cellular proliferation and differentiation. In addition, aberrant ERalpha activity is linked to several pathological conditions including breast cancer. A c ... Full text Link to item Cite

Ligand-selective interactions of ER detected in living cells by fluorescence resonance energy transfer.

Journal Article Mol Endocrinol · March 2002 Some aspects of ligand-regulated transcription activation by the estrogen receptor (ER) are associated with the estrogen-dependent formation of a hydrophobic cleft on the receptor surface. At least in vitro, this cleft is required for direct interaction of ... Full text Link to item Cite

Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements.

Journal Article Mol Endocrinol · March 2002 Hormone-activated ERs (ERalpha and ERbeta) bind with high affinity to specific DNA sequences, estrogen response elements (EREs), located within the regulatory regions of target genes. Once considered to function solely as receptor tethers, there is an incr ... Full text Link to item Cite

Definition of the molecular and cellular mechanisms underlying the tissue-selective agonist/antagonist activities of selective estrogen receptor modulators.

Journal Article Recent Prog Horm Res · 2002 The term selective estrogen receptor modulators describes a group of pharmaceuticals that function as estrogen receptor (ER) agonists in some tissues but that oppose estrogen action in others. Although the name for this class of drugs has been adopted only ... Full text Link to item Cite

Glucocorticoids manifest androgenic activity in a cell line derived from a metastatic prostate cancer.

Journal Article Cancer Res · December 15, 2001 The pathophysiological mechanism(s) by which androgen independence develops in prostate cancer remains to be determined. The identification in many prostate cancer specimens of a mutant androgen receptor, T877A, with altered ligand specificity has provided ... Link to item Cite

Capitalizing on the complexities of estrogen receptor pharmacology in the quest for the perfect SERM.

Journal Article Ann N Y Acad Sci · December 2001 The term Selective Estrogen Receptor Modulators (SERMs) has been used of late to describe a group of pharmaceuticals that manifest estrogen receptor (ER) agonist activity in some tissues, but that oppose estrogen action in others. Whereas the name describi ... Full text Link to item Cite

Development of an ER action indicator mouse for the study of estrogens, selective ER modulators (SERMs), and Xenobiotics.

Journal Article Endocrinology · November 2001 We have developed a transgenic mouse that functions as a reporter of ER activity, termed ER action indicator (ERIN), by incorporating a transgene with an estrogen-responsive promoter (three copies of the vitellogenin estrogen response element with a minima ... Full text Link to item Cite

The human estrogen receptor-alpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators.

Journal Article J Biol Chem · September 21, 2001 The human estrogen receptor alpha-isoform (ERalpha) is a nuclear transcription factor that displays a complex pharmacology. In addition to classical agonists and antagonists, the transcriptional activity of ERalpha can be regulated by selective estrogen re ... Full text Link to item Cite

Nuclear import/export of hRPF1/Nedd4 regulates the ubiquitin-dependent degradation of its nuclear substrates.

Journal Article J Biol Chem · July 13, 2001 The ubiquitin-protein ligase (E3), hRPF1/Nedd4, is a component of the ubiquitin-proteasome pathway responsible for substrate recognition and specificity. Although previously characterized as a regulator of the stability of cytoplasmic proteins, hRPF1/Nedd4 ... Full text Link to item Cite

Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor.

Journal Article Cancer Res · April 1, 2001 Tamoxifen inhibits estrogen receptor (ER) transcriptional activity by competitively inhibiting estradiol binding and inducing conformational changes in the receptor that may prevent its interaction with coactivators. In bone, the cardiovascular system, and ... Link to item Cite

Toxicology of environmental estrogens.

Journal Article Reprod Fertil Dev · 2001 It has been hypothesized that environmental contaminants that modulate endocrine signaling pathways may be causally linked to adverse health effects in humans. There has been particular concern regarding synthetic estrogens and their role in disrupting nor ... Full text Link to item Cite

Development of peptide antagonists that target estrogen receptor beta-coactivator interactions.

Journal Article Mol Endocrinol · December 2000 The biological actions of estrogen are manifest through two genetically distinct estrogen receptors (ER alpha and ER beta) that display nonidentical expression patterns in target tissues. The phenotypic alterations in response to estrogens in mice disrupte ... Full text Link to item Cite

Temporally distinct and ligand-specific recruitment of nuclear receptor-interacting peptides and cofactors to subnuclear domains containing the estrogen receptor.

Journal Article Mol Endocrinol · December 2000 Ligand binding to estrogen receptor (ER) is presumed to regulate the type and timing of ER interactions with different cofactors. Using fluorescence microscopy in living cells, we characterized the recruitment of five different green fluorescent protein (G ... Full text Link to item Cite

Development of peptide antagonists that target estrogen receptor-cofactor interactions.

Journal Article J Steroid Biochem Mol Biol · November 30, 2000 We have developed a series of high-affinity peptide antagonists that inhibit the transcriptional activity of both subtypes of the human estrogen receptor (ERalpha and ERbeta). We believe that it will be possible to develop these peptides, or corresponding ... Full text Link to item Cite

Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: structure-activity studies.

Journal Article Mol Pharmacol · October 2000 We previously demonstrated differential interactions of the methoxychlor metabolite 2,2-bis(p-hydroxyphenyl)-1,1, 1-trichloroethane (HPTE) with estrogen receptor alpha (ERalpha), ERbeta, and the androgen receptor (AR). In this study, we characterize the ER ... Link to item Cite

Modulation of estrogen receptor-alpha transcriptional activity by the coactivator PGC-1.

Journal Article J Biol Chem · May 26, 2000 A transcriptional coactivator of the peroxisome proliferator-activated receptor-gamma (PPARgamma), PPARgamma-coactivator-1(PGC-1) interacts in a constitutive manner with the hinge domain of PPARgamma and enhances its transcriptional activity. In this study ... Full text Link to item Cite

The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding.

Journal Article Mol Cell Biol · May 2000 The human progesterone receptor (PR) exists as two functionally distinct isoforms, hPRA and hPRB. hPRB functions as a transcriptional activator in most cell and promoter contexts, while hPRA is transcriptionally inactive and functions as a strong ligand-de ... Full text Link to item Cite

Selective estrogen receptor modulators (SERMs): A first step in the development of perfect hormone replacement therapy regimen.

Journal Article J Soc Gynecol Investig · 2000 Until 1986, our understanding of estrogen receptor (ER) action was based on information derived from in vitro biochemical analyses and in vivo correlations. With the cloning of the human ER cDNA, the reconstitution of ER responsive transcription units in h ... Full text Link to item Cite

Comparative analyses of mechanistic differences among antiestrogens.

Journal Article Endocrinology · December 1999 Antiestrogens such as tamoxifen are one of the most effective methods of treating estrogen receptor (ERalpha) positive breast cancers; however, the effectiveness of this therapy is limited by the almost universal development of resistance to the drug. If a ... Full text Link to item Cite

Dissection of the LXXLL nuclear receptor-coactivator interaction motif using combinatorial peptide libraries: discovery of peptide antagonists of estrogen receptors alpha and beta.

Journal Article Mol Cell Biol · December 1999 Recruitment of transcriptional coactivators following ligand activation is a critical step in nuclear receptor-mediated target gene expression. Upon binding an agonist, the receptor undergoes a conformational change which facilitates the formation of a spe ... Full text Link to item Cite

Differential interaction of the methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane with estrogen receptors alpha and beta.

Journal Article Endocrinology · December 1999 Concern that some chemicals in our environment may affect human health by disrupting normal endocrine function has prompted research on interactions of environmental contaminants with steroid hormone receptors. We compared the activity of 2,2-bis-(p-hydrox ... Full text Link to item Cite

The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens.

Journal Article Endocrinology · December 1999 The human estrogen receptor alpha (ERalpha) and the recently identified ERbeta share a high degree of amino acid homology; however, there are significant differences in regions of these receptors that would be expected to influence transcriptional activity ... Full text Link to item Cite

The Molecular Pharmacology of SERMs.

Journal Article Trends Endocrinol Metab · October 1999 Estrogen-containing medicines have been used successfully for the past 50 years for the treatment of conditions associated with menopause. Although initially considered a reproductive hormone, millions of years of clinical exposure to estrogen(s) have indi ... Full text Link to item Cite

Rsp5 ubiquitin-protein ligase mediates DNA damage-induced degradation of the large subunit of RNA polymerase II in Saccharomyces cerevisiae.

Journal Article Mol Cell Biol · October 1999 Rsp5 is an E3 ubiquitin-protein ligase of Saccharomyces cerevisiae that belongs to the hect domain family of E3 proteins. We have previously shown that Rsp5 binds and ubiquitinates the largest subunit of RNA polymerase II, Rpb1, in vitro. We show here that ... Full text Link to item Cite

Peptide antagonists of the human estrogen receptor.

Journal Article Science · July 30, 1999 Estrogen receptor alpha transcriptional activity is regulated by distinct conformational states that are the result of ligand binding. Phage display was used to identify peptides that interact specifically with either estradiol- or tamoxifen-activated estr ... Full text Link to item Cite

Hormone-dependent interaction between the amino- and carboxyl-terminal domains of progesterone receptor in vitro and in vivo.

Journal Article Mol Endocrinol · June 1999 Full transcriptional activation by steroid hormone receptors requires functional synergy between two transcriptional activation domains (AF) located in the amino (AF-1) and carboxyl (AF-2) terminal regions. One possible mechanism for achieving this functio ... Full text Link to item Cite

Estrogen-induced activation of mitogen-activated protein kinase requires mobilization of intracellular calcium.

Journal Article Proc Natl Acad Sci U S A · April 13, 1999 Estrogens and growth factors such as epidermal growth factor (EGF) act as mitogens promoting cellular proliferation in the breast and in the reproductive tract. Although it was considered originally that these agents manifested their mitogenic actions thro ... Full text Link to item Cite

Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta.

Journal Article Proc Natl Acad Sci U S A · March 30, 1999 Estrogen receptor (ER) modulators produce distinct tissue-specific biological effects, but within the confines of the established models of ER action it is difficult to understand why. Previous studies have suggested that there might be a relationship betw ... Full text Link to item Cite

The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene.

Journal Article Recent Prog Horm Res · 1999 In humans, the biological response to progesterone is mediated by two forms of the progesterone receptor (hPR-A; 94kDa and hPR-B; 114kDa). These two isoforms are transcribed from distinct, estrogen-inducible promoters within a single-copy progesterone rece ... Link to item Cite

Wyeth lederle recent advances in conjugated estrogens estrogen action 1998: new insights. new drugs, new issues

Journal Article International Journal of Fertility and Menopausal Studies · December 1, 1998 Cite

Bisphenol A interacts with the estrogen receptor alpha in a distinct manner from estradiol.

Journal Article Mol Cell Endocrinol · July 25, 1998 We investigated the interaction of bisphenol A (BPA, an estrogenic environmental contaminant used in the manufacture of plastics) with the estrogen receptor alpha (ERalpha) transfected into the human HepG2 hepatoma cell line and expanded the study in vivo ... Full text Link to item Cite

Inhibition of androgen receptor-dependent transcriptional activity by DDT isomers and methoxychlor in HepG2 human hepatoma cells.

Journal Article Toxicol Appl Pharmacol · July 1998 Recent reports have raised new concerns that chemicals in our environment may disrupt normal reproduction and development through inhibition of androgen receptor function. This heightened concern has also increased our need for methods that allow us to cha ... Full text Link to item Cite

Potency of combined estrogenic pesticides: Synergy between synthetic oestrogens?

Journal Article Chemtracts · April 1, 1998 These studies each show that certain binary mixtures of weak, environmental estrogens act additively. The results were obtained by testing mixtures of these compounds in a variety of estrogen assays. These studies were prompted by a now retracted report th ... Cite

Enhancement of estrogen receptor transcriptional activity by the coactivator GRIP-1 highlights the role of activation function 2 in determining estrogen receptor pharmacology.

Journal Article J Biol Chem · March 20, 1998 The human estrogen receptor (ER) contains two major activation functions (AFs) responsible for its transcriptional activity. One of these, activation function 2 (AF-2), located within the hormone-binding domain (HBD), has been shown to mediate the ligand-d ... Full text Link to item Cite

The nuclear corepressors NCoR and SMRT are key regulators of both ligand- and 8-bromo-cyclic AMP-dependent transcriptional activity of the human progesterone receptor.

Journal Article Mol Cell Biol · March 1998 Previously, we defined a novel class of ligands for the human progesterone receptor (PR) which function as mixed agonists. These compounds induce a conformational change upon binding the receptor that is different from those induced by agonists and antagon ... Full text Link to item Cite

Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor.

Journal Article J Biol Chem · December 26, 1997 In humans, the biological response to progesterone is mediated by two distinct forms of the progesterone receptor (human (h) PR-A, 94 kDa and hPR-B, 114 kDa). These two isoforms are transcribed from distinct estrogen-inducible promoters within a single cop ... Full text Link to item Cite

Additive estrogenic activities of a binary mixture of 2',4',6'-trichloro- and 2',3',4',5'-tetrachloro-4-biphenylol.

Journal Article Toxicol Appl Pharmacol · November 1997 The estrogenic activity of 2',4',6'-trichloro-4-biphenylol (HO-PCB3), 2',3',4',5'-tetrachloro-4-biphenylol (HO-PCB4), and an equimolar mixture of both compounds (HO-PCB3/HO-PCB4) was investigated in the 21-day-old B6C3F1 mouse uterus, MCF-7 and MDA-MB-231 ... Full text Link to item Cite

Dissection of the molecular mechanism of action of GW5638, a novel estrogen receptor ligand, provides insights into the role of estrogen receptor in bone.

Journal Article Endocrinology · September 1997 The estrogen receptor (ER) mixed agonists tamoxifen and raloxifene have been shown to protect against bone loss in ovariectomized rats. However, the mechanism by which these compounds manifest their activity in bone is unknown. We have used a series of in ... Full text Link to item Cite

Evaluation of a recombinant yeast cell estrogen screening assay.

Journal Article Environ Health Perspect · July 1997 A wide range of chemicals with diverse structures derived from plant and environmental origins are reported to have hormonal activity. The potential for appreciable exposure of humans to such substances prompts the need to develop sensitive screening metho ... Full text Link to item Cite

Identification of a third autonomous activation domain within the human estrogen receptor.

Journal Article Mol Endocrinol · June 1997 Using a genetic selection system established in the yeast Saccharomyces cerevisiae, we have isolated, by random mutagenesis of the human estrogen receptor (ER), six mutants that display constitutive transcriptional activity. All of the mutants identified c ... Full text Link to item Cite

Estrogenic activity of a dieldrin/toxaphene mixture in the mouse uterus, MCF-7 human breast cancer cells, and yeast-based estrogen receptor assays: no apparent synergism.

Journal Article Endocrinology · April 1997 The estrogenic activity of dieldrin, toxaphene, and an equimolar mixture of both compounds (dieldrin/toxaphene) was investigated in the 21-day-old B6C3F1 mouse uterus, MCF-7 human breast cancer cells, and in yeast-based reporter gene assays. Treatment of t ... Full text Link to item Cite

Evaluation of chemicals with endocrine modulating activity in a yeast-based steroid hormone receptor gene transcription assay.

Journal Article Toxicol Appl Pharmacol · March 1997 There is a concern that chemicals in our environment are affecting human health by disrupting normal endocrine function. Much of the concern has focused on chemicals that can interact directly with steroid hormone receptors. We have used a yeast-based assa ... Full text Link to item Cite

Potency of combined estrogenic pesticides.

Journal Article Science · January 17, 1997 Full text Link to item Cite

BRCA1 expression is not directly responsive to estrogen.

Journal Article Oncogene · January 9, 1997 Expression of the breast cancer susceptibility gene, BRCA1, is induced by 17-beta estradiol (E2) in estrogen receptor containing breast cancer cell lines. Our previous studies have shown that BRCA1 transcription is also regulated with the cell cycle, reach ... Full text Link to item Cite

Identification of the sequences within the human complement 3 promoter required for estrogen responsiveness provides insight into the mechanism of tamoxifen mixed agonist activity.

Journal Article Mol Endocrinol · December 1996 The promoter of the human C3 gene has been shown to be responsive to stimulation by both estrogen and tamoxifen-activated estrogen receptor (ER) in transcriptional assays reconstituted in mammalian cells. Using a series of deletions and point mutations, we ... Full text Link to item Cite

16 alpha-substituted analogs of the antiprogestin RU486 induce a unique conformation in the human progesterone receptor resulting in mixed agonist activity.

Journal Article Proc Natl Acad Sci U S A · August 6, 1996 Previously, we have shown that agonists and antagonists interact with distinct, though overlapping regions within the human progesterone receptor (hPR) resulting in the formation of structurally different complexes. Thus, a link was established between the ... Full text Link to item Cite

Yeast RSP5 and its human homolog hRPF1 potentiate hormone-dependent activation of transcription by human progesterone and glucocorticoid receptors.

Journal Article Mol Cell Biol · June 1996 We have developed a system in Saccharomyces cerevisiae in which agonist-dependent transcriptional activity of the human progesterone receptor (hPR) is elevated to the point that it compromises cell growth. Screens for suppressors of this phenotype led to t ... Full text Link to item Cite

Impact of process changes on the physical properties and formability of silver metal oxide contact materials

Journal Article Electrical Contacts, Proceedings of the Annual Holm Conference on Electrical Contacts · December 1, 1995 The physical characteristics of electrical contact materials are influenced by the method and process parameters used in their manufacture. This study examines internally oxidized silver metal oxide contact materials manufactured using two casting methods ... Cite

Identification of a new subclass of Alu DNA repeats which can function as estrogen receptor-dependent transcriptional enhancers.

Journal Article J Biol Chem · September 29, 1995 We have utilized a genetic selection system in yeast to identify novel estrogen-responsive genes within the human genome and to define the sequences in the BRCA-1 gene responsible for its estrogen responsiveness. This approach led to the identification of ... Full text Link to item Cite

Cellular mechanisms which distinguish between hormone- and antihormone-activated estrogen receptor.

Journal Article Ann N Y Acad Sci · June 12, 1995 The use of reverse genetics has permitted a definition of the structural features within estrogen receptor required for its productive association with the transcription apparatus. These sequences, transactivation function 1 (TAF1) in the amino terminus an ... Full text Link to item Cite

Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens.

Journal Article Mol Endocrinol · June 1995 We have developed a series of in vitro models with which to evaluate the biological activity of estrogen receptor (ER) agonists and antagonists. Using a protease digestion assay we show that the conformational changes induced within ER are distinct for ago ... Full text Link to item Cite

Definition of the critical cellular components which distinguish between hormone and antihormone activated progesterone receptor.

Journal Article J Steroid Biochem Mol Biol · June 1995 The steroid hormone progesterone is a key modulator of the cellular processes associated with the maintenance and development of female reproductive function. The biological activity of this hormone is mediated by specific nuclear receptors located in targ ... Full text Link to item Cite

Unraveling the human progesterone receptor signal transduction pathway Insights into antiprogestin action.

Journal Article Trends Endocrinol Metab · 1995 The steroid hormone progesterone is a key modulator of the cellular processes that are required for the development and maintenance of reproductive function. Produced primarily by ovarian granulosa cells, it mediates its biological activity throughout the ... Full text Link to item Cite

Advances in our understanding of ligand-activated nuclear receptors

Journal Article Current Opinion in Biotechnology · January 1, 1995 During the past year, our understanding of signal transduction pathways mediated by nuclear receptors has advanced significantly. Progress was due, in part, to the identification of ligands for orphan receptors, to the discovery of proteins that interact w ... Full text Cite

Development of tissue-selective estrogen receptor modulators

Conference ORGAN-SELECTIVE ACTIONS OF STEROID HORMONES · January 1, 1995 Link to item Cite

Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay.

Journal Article J Clin Invest · December 1994 We hypothesized that estradiol levels are higher in prepubertal girls than in prepubertal boys and that this greater secretion of estradiol might drive the more rapid epiphyseal development and earlier puberty in girls. Since previous estradiol assays have ... Full text Link to item Cite

Comparison of the switching behavior of internally oxidized and powder metallurgical silver metal oxide contact materials

Journal Article Electrical Contacts, Proceedings of the Annual Holm Conference on Electrical Contacts · December 1, 1994 The switching behavior of powder metallurgical and internally oxidized silver tin oxide based and silver cadmium oxide based contact materials was compared. Computer supported analysis of contact performance (contact weld force, changes in electrical resis ... Cite

The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells.

Journal Article Mol Cell Biol · December 1994 The biological response to progesterone is mediated by two distinct forms of the human progesterone receptor (hPR-A and hPR-B). In most cell contexts, hPR-B functions as a transcriptional activator of progesterone-responsive genes, whereas hPR-A functions ... Full text Link to item Cite

Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators.

Journal Article J Steroid Biochem Mol Biol · November 1994 We have isolated a human peroxisomal proliferator activated receptor (hPPAR) from a human liver cDNA library. Based on sequence analysis, we have determined that this cDNA encodes the human PPAR alpha. When assayed in a reconstituted hPPAR responsive trans ... Full text Link to item Cite

Definition of the cellular mechanisms which distinguish between hormone and antihormone activated steroid receptors.

Journal Article Semin Cancer Biol · October 1994 Steroid hormones are key regulatory molecules required for the coordinated regulation of the events associated with growth, differentiation and maintenance of cellular homeostasis. A large number of clinical abnormalities have been shown to be associated w ... Link to item Cite

Potentiation of progesterone receptor-mediated transcription by the immunosuppressant FK506.

Journal Article Biochemistry · September 6, 1994 The nontransformed steroid receptors contain several non-steroid binding proteins, such as hsp90, hsp70, and p59. Recently, we and others have shown that p59 (FKBP59) is an immunophilin which binds two potent immunosuppressants, FK506 and rapamycin. This r ... Full text Link to item Cite

Novel estrogen response elements identified by genetic selection in yeast are differentially responsive to estrogens and antiestrogens in mammalian cells.

Journal Article Mol Endocrinol · September 1994 A powerful and versatile system for the identification of novel response elements for members of the intracellular receptor family is presented as applied to the human estrogen receptor. In the past, a limited number of estrogen response elements (EREs) ha ... Full text Link to item Cite

Creatine kinase activity as an indicator of unopposed estrogen action in the mouse uterus associated with anti-progesterone treatment.

Journal Article J Steroid Biochem Mol Biol · June 1994 The brain isozyme of creatine kinase (CKB) is a major component of the estrogen-induced proteins in the rat uterus. Hormonal specificity of this response was studied in cotransfection assays using the rat CKB promoter linked to the bacterial chloramphenico ... Full text Link to item Cite

RU486 exerts antiestrogenic activities through a novel progesterone receptor A form-mediated mechanism.

Journal Article J Biol Chem · April 22, 1994 The human progesterone receptor (hPR) exists in two distinct forms in most cells, hPR-A and hPR-B. Both receptor isoforms exhibit distinct biological functions and demonstrate a cell- and promoter-specific ability to regulate gene transcription. Interestin ... Link to item Cite

The human progesterone receptor A-form functions as a transcriptional modulator of mineralocorticoid receptor transcriptional activity.

Journal Article J Steroid Biochem Mol Biol · April 1994 The human progesterone receptor (hPR) exists as two distinct molecular forms in most cells, hPR-A and -B. These receptor isoforms display distinct biological functions and demonstrate a cell and promoter specific ability to regulate gene transcription. In ... Full text Link to item Cite

Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions.

Journal Article Mol Endocrinol · January 1994 We have used a series of human estrogen receptor (ER) mutants to evaluate the cell- and promoter-specific transcriptional activities of the TAF1 and TAF2 transactivation regions within the human ER. We show that the manifestation of TAF1 or TAF2 function d ... Full text Link to item Cite

Comparison of the switching behavior of silver metal oxide contact materials

Journal Article Electrical Contacts, Proceedings of the Annual Holm Conference on Electrical Contacts · December 1, 1993 An investigation of the switching behavior of internally oxidized silver cadmium oxide and silver tin, indium oxide contact materials was undertaken in which detailed, computer supported analysis of changes in the performance (contact weld force, electrica ... Cite

The mechanism of action of steroid hormones: a new twist to an old tale.

Journal Article J Clin Pharmacol · December 1993 Steroid hormones, vitamins, and thyroid hormone are potent chemical messengers that exert dramatic effects on cell differentiation, homeostasis, and morphogenesis. These molecules, though diverse in structure, share a mechanistically similar mode of action ... Full text Link to item Cite

Nuclear hormone receptors as targets for new drug discovery.

Journal Article Biotechnology (N Y) · November 1993 There are two basic types of receptor transducing systems: those which utilize membrane bound receptors and are activated at the cell surface by the appropriate hormone and transmit their signal to the internae of the cell via a second messenger (i.e. cAMP ... Full text Link to item Cite

Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function.

Journal Article Mol Endocrinol · October 1993 Two distinct isoforms of the human progesterone receptor (hPR-A and hPR-B) have been identified previously. They differ only in that hPR-B contains an additional 164 amino acids at the amino terminus. Among various species these two forms arise as a result ... Full text Link to item Cite

Expression of recombinant human methylmalonyl-CoA mutase: in primary mut fibroblasts and Saccharomyces cerevisiae.

Journal Article Biochem Med Metab Biol · October 1993 Methylmalonyl-CoA mutase is an adenosylcobalamin-dependent enzyme which catalyzes isomerization of methylmalonyl-CoA to succinyl-CoA. Previous reports have described cloning and sequencing of a cDNA for human methylmalonyl-CoA mutase. This clone does not e ... Full text Link to item Cite

Chicken progesterone receptor expressed in Saccharomyces cerevisiae is correctly phosphorylated at all four Ser-Pro phosphorylation sites.

Journal Article Biochemistry · September 21, 1993 This study describes the phosphorylation of chicken progesterone receptor (cPR) produced in yeast, Saccharomyces cerevisiae, and examines the dependence of specific phosphorylations on hormone and DNA binding. The chicken progesterone receptor is expressed ... Full text Link to item Cite

Positive regulation of the vitamin D receptor by its cognate ligand in heterologous expression systems.

Journal Article Mol Endocrinol · July 1993 Hormonal vitamin D3 is a major regulator of calcium metabolism and is involved in basic cellular processes, such as those of proliferation and differentiation. These actions are mediated via an intracellular vitamin D3 receptor (VDR), which is a member of ... Full text Link to item Cite

Creation of an active estrogen-responsive element by a single base change in the flanking sequence of a cellular oncogene: a possible mechanism for hormonal carcinogenesis?

Journal Article Mol Carcinog · 1993 Estrogens are considered to act as promoters in a multistep process of hormonal carcinogenesis, although the molecular mechanisms by which these hormones act in tumorigenesis are unclear at present. Estradiol is known to induce expression of certain proto- ... Full text Link to item Cite

Identification of a negative regulatory function for steroid receptors.

Journal Article Proc Natl Acad Sci U S A · November 15, 1992 This report describes the identification of a negative regulator of estrogen and progesterone receptor function. Using a reconstituted estrogen-responsive transcription system in Saccharomyces cerevisiae, we have identified a "repressor function," which wh ... Full text Link to item Cite

Identification of an estrogen response element in the 3'-flanking region of the murine c-fos protooncogene.

Journal Article J Biol Chem · September 5, 1992 We have used transient transfection assays with reporter plasmids expressing chloramphenicol acetyltransferase, linked to regions of mouse c-fos, to identify a specific estrogen response element (ERE) in this protooncogene. This element is located in the u ... Link to item Cite

Ligand-dependent and -independent function of the transactivation regions of the human estrogen receptor in yeast.

Journal Article Mol Endocrinol · July 1992 The estrogen receptor (ER) is a transcription factor involved in steroid hormone signal transduction in higher eukaryotes. The receptor also functions as a ligand-dependent transcriptional activator when introduced into Saccharomyces cerevisiae (baker's ye ... Full text Link to item Cite

Structural requirements for high affinity ligand binding by estrogen receptors: a comparative analysis of truncated and full length estrogen receptors expressed in bacteria, yeast, and mammalian cells.

Journal Article Mol Endocrinol · June 1992 In order to better understand the structural requirements for effective high affinity binding of estrogens and antiestrogens by the human estrogen receptor (ER), a comparative study was undertaken in which we examined: 1) native ER from the MCF-7 ER-positi ... Full text Link to item Cite

The mechanism of RU486 antagonism is dependent on the conformation of the carboxy-terminal tail of the human progesterone receptor.

Journal Article Cell · May 15, 1992 The human progesterone receptor form B (hPR-B) was expressed in Saccharomyces cerevisiae together with a specific reporter plasmid. To understand the mechanism underlying antagonist ligand activity, libraries of hormone binding domain (HBD)-mutated hPR-B m ... Full text Link to item Cite

A novel, highly regulated, rapidly inducible system for the expression of chicken progesterone receptor, cPRA, in Saccharomyces cerevisiae.

Journal Article Gene · May 1, 1992 A rapidly inducible and tightly regulated system for the expression of protein in yeast is based on a chimeric promoter constructed of two copies of a vitellogenin-estrogen-response element (ERE) which are inserted upstream from the promoter of the yeast g ... Full text Link to item Cite

Modulation of progesterone receptor binding to progesterone response elements by positioned nucleosomes.

Journal Article Biochemistry · February 11, 1992 In cells, steroid hormone receptors interact with target enhancer elements on nucleosomes to regulate transcription of genes. To elucidate how nucleosomes can potentially regulate the interactions of steroid receptors with steroid response elements, we hav ... Full text Link to item Cite

Inhibition of estrogen receptor action by a naturally occurring variant in human breast tumors

Journal Article Cancer Research · 1992 It is fairly well accepted that the presence of estrogen receptor (ER) and progesterone receptor (PgR) identifies breast cancer patients with a lower risk of relapse and better overall survival. But patients with discordant receptors, the ER+/PgR- phenotyp ... Cite

Identification of novel steroid-response elements.

Journal Article Gene Expr · 1992 A rapid method for defining novel steroid-responsive elements has been developed. Large libraries of degenerate oligonucleotides were analyzed using a yeast-based screen to identify estrogen-responsive DNA sequences. From a library of 40,000 recombinants, ... Link to item Cite

Transactivation functions facilitate the disruption of chromatin structure by estrogen receptor derivatives in vivo.

Journal Article J Biol Chem · September 25, 1991 The activation of gene transcription by nuclear receptors is invariably associated with alterations in chromatin structure at hormone-responsive elements of target genes. To identify the molecular functions underlying receptor-mediated chromatin structure ... Link to item Cite

In situ distinction between steroid receptor binding and transactivation at a target gene.

Journal Article Mol Cell Biol · September 1991 We have developed a DNA interference assay in the yeast Saccharomyces cerevisiae that is designed to indicate the intracellular DNA-binding status of the estrogen receptor. The assay utilizes a promoter containing multiple copies of a GAL4-estrogen recepto ... Full text Link to item Cite

High level expression of biologically active estrogen receptor in Saccharomyces cerevisiae.

Journal Article J Steroid Biochem Mol Biol · September 1991 Biochemical over-expression of the human estrogen receptor was achieved using a Saccharomyces cerevisiae expression system. The receptor was produced as a novel ubiquitin fusion protein. This fusion protein is short lived in the cell and is processed to pr ... Full text Link to item Cite

Antiestrogen can establish nonproductive receptor complexes and alter chromatin structure at target enhancers.

Journal Article Proc Natl Acad Sci U S A · April 15, 1991 We describe in this report experiments in vivo that demonstrate that antiestrogens promote DNA binding of the estrogen receptor without efficiently inducing transcription. When the receptor is modified to carry a foreign unregulated transactivation domain, ... Full text Link to item Cite

Variant human breast tumor estrogen receptor with constitutive transcriptional activity

Journal Article Cancer Research · 1991 Since progesterone receptor (PgR) is normally induced by estrogen, breast cancers lacking estrogen receptor (ER) would also be expected to lack PgR. However, a small percentage of breast cancers are ER- yet PgR+. These tumors might possess an ER which is d ... Cite

Expression of human vitamin D receptor in Saccharomyces cerevisiae. Purification, properties, and generation of polyclonal antibodies.

Journal Article J Biol Chem · December 15, 1990 We have cloned a cDNA encoding the human vitamin D receptor (VDR) into a high copy yeast plasmid controlled transcriptionally by the copper-inducible metallothionein (CUP-1) promoter to produce YEpV1. Introduction of this plasmid in the protease deficient ... Link to item Cite

Vitamin D receptor interaction with specific DNA requires a nuclear protein and 1,25-dihydroxyvitamin D3.

Journal Article Proc Natl Acad Sci U S A · December 1990 The regulation of osteocalcin gene expression by 1,25-dihydroxyvitamin D3 is mediated by the vitamin D receptor and a cis-acting DNA response element that has been identified within the 5' region of the osteocalcin promoter. In this report, we show that vi ... Full text Link to item Cite

High level expression of a truncated chicken progesterone receptor in Escherichia coli.

Journal Article J Biol Chem · January 25, 1990 Using a novel Escherichia coli system we have successfully overexpressed a region of the chicken progesterone receptor which encodes both the DNA- and hormone-binding domains. The expression system produces the truncated receptor fragment as an in-frame fu ... Link to item Cite

Expression of functional chicken oviduct progesterone receptors in yeast (Saccharomyces cerevisiae).

Journal Article J Biol Chem · December 25, 1989 The cDNAs encoding full-length chicken oviduct progesterone receptor B (PRB) and a truncated receptor (C1C2) lacking the amino-terminal domain were expressed in yeast (Saccharomyces cerevisiae) using a ubiquitin fusion system. The expression of the fusion ... Link to item Cite

Reconstitution of the vitamin D-responsive osteocalcin transcription unit in Saccharomyces cerevisiae.

Journal Article Mol Cell Biol · August 1989 The human osteocalcin gene is regulated in mammalian osteoblasts by 1,25(OH)2D3-dependent and -independent mechanisms. The sequences responsible for this activity have been mapped to within the -1339 region of the gene. We show here that this enhancer regi ... Full text Link to item Cite

Functional domains of the human vitamin D3 receptor regulate osteocalcin gene expression.

Journal Article Mol Endocrinol · April 1989 The human vitamin D receptor (VDR) has been cloned recently. Two cDNAs comprising the full-length VDR were spliced, cloned into a mammalian expression vector, and transiently expressed in COS-1 cells. The protein product exhibited properties consistent wit ... Full text Link to item Cite

Cloning and expression of full-length cDNA encoding human vitamin D receptor.

Journal Article Proc Natl Acad Sci U S A · May 1988 Complementary DNA clones encoding the human vitamin D receptor have been isolated from human intestine and T47D cell cDNA libraries. The nucleotide sequence of the 4605-base pair (bp) cDNA includes a noncoding leader sequence of 115 bp, a 1281-bp open read ... Full text Link to item Cite

Molecular biology of the vitamin D hormone.

Journal Article Recent Prog Horm Res · 1988 Full text Link to item Cite

The vitamin D receptor: a primitive steroid receptor related to thyroid hormone receptor.

Journal Article J Steroid Biochem · 1988 We have previously reported the cloning and sequencing of both the chicken and human vitamin D3 receptor cDNAs. A comparison of their deduced amino acid sequence with that of the other classic steroid hormone receptors and the receptor for thyroid hormone ... Full text Link to item Cite

Immunoselection of cDNAs to avian intestinal calcium binding protein 28K and a novel calmodulin-like protein: assessment of mRNA regulation by the vitamin D hormone.

Journal Article Biochemistry · December 15, 1987 Calcium's role in a variety of cellular processes has been well documented. The storage, distribution, and delivery of calcium are regulated by a family of binding proteins including troponin C, calmodulin, parvalbumin, and vitamin D dependent calcium bind ... Full text Link to item Cite

Molecular cloning of complementary DNA encoding the avian receptor for vitamin D.

Journal Article Science · March 6, 1987 Vitamin D3 receptors are intracellular proteins that mediate the nuclear action of the active metabolite 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Two receptor-specific monoclonal antibodies were used to recover the complementary DNA (cDNA) of this regulator ... Full text Link to item Cite

Structural organization and regulation of the chicken estrogen receptor.

Journal Article Mol Endocrinol · January 1987 We have cloned the chicken estrogen receptor (ER) from a chicken oviduct lambda gt11 library using the human ER cDNA sequence. This chicken ER sequence is virtually identical to the recently published sequence. One noteable difference is an amino acid chan ... Full text Link to item Cite

Analysis of repetitive sequence elements containing tRNA-like sequences.

Journal Article Nucleic Acids Res · June 25, 1985 Several repetitive sequence elements from diverse species share extensive sequence homology with tRNA molecules. Analysis of the tRNA-like sequences within these elements suggest that they have originated from authentic tRNA sequences. Elements containing ... Full text Link to item Cite