Scholars@Duke
Suzanne E Wardell

Suzanne E Wardell

Assistant Research Professor of Pharmacology and Cancer Biology
Pharmacology & Cancer Biology
suzanne.wardell@duke.edu
Box 3813 Med Ctr, Durham, NC 27710
LSRC. C-248, Durham, NC 27710

Selected Publications

PKN2 is a dependency of the mesenchymal-like cancer cell state.

Journal Article Cancer Discov · November 19, 2024 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. Here, we systematically identify the depend ... Full text Link to item 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

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

Journal Article Nat Commun · September 3, 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 Link to item Cite

UDP-6-glucose dehydrogenase in hormonally responsive breast cancers.

Journal Article bioRxiv · March 21, 2024 Survival for metastatic breast cancer is low and thus, continued efforts to treat and prevent metastatic progression are critical. Estrogen is shown to promote aggressive phenotypes in multiple cancer models irrespective of estrogen receptor (ER) status. S ... Full text Link to item 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

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

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

Cellphone enabled point-of-care assessment of breast tumor cytology and molecular HER2 expression from fine-needle aspirates.

Journal Article NPJ Breast Cancer · July 2, 2021 Management of breast cancer in limited-resource settings is hindered by a lack of low-cost, logistically sustainable approaches toward molecular and cellular diagnostic pathology services that are needed to guide therapy. To address these limitations, we h ... 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

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer.

Journal Article Breast Cancer Res Treat · April 2020 PURPOSE: The combination of targeting the CDK4/6 and estrogen receptor (ER) signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment of ER-positive breast cancer. However, the poor physicochemical properties of ... 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 Res Treat · January 2020 PURPOSE: Fulvestrant 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 of meta ... 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

Genomically informed small-molecule drugs overcome resistance to a sustained-release formulation of an engineered death receptor agonist in patient-derived tumor models.

Journal Article Sci Adv · September 2019 Extrinsic pathway agonists have failed repeatedly in the clinic for three core reasons: Inefficient ligand-induced receptor multimerization, poor pharmacokinetic properties, and tumor intrinsic resistance. Here, we address these factors by (i) using a high ... 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

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

Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer.

Journal Article Cancer Discov · September 2018 Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast c ... Full text Link to item Cite

Abstract 1805: Development of a selective androgen receptor degrader (SARD) for treatment of castration-resistant prostate cancer

Conference Cancer Research · July 1, 2018 AbstractCurrent treatments for prostate cancer are centered on blocking androgen-signaling axis, which is the target of several clinical androgen receptor (AR) antagonists such as enzalutamide. Recent studie ... Full text 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

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

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

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

Discovery of a selective androgen receptor degrader (SARD) for treatment of castration-resistant prostate cancer

Conference ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY · August 20, 2017 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

A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution.

Journal Article Cell Rep · July 25, 2017 Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematical ... Full text Link to item Cite

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

Journal Article Oncogene · July 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 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

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

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

SERMs and SERDs as the cornerstone of endocrine therapy in ER alpha-positive breast cancer

Conference ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY · August 20, 2016 Link to item Cite

Targeting protein-protein interactions for disruption of KDM1A (LSD1) complexes

Conference ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY · March 13, 2016 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

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

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

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

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

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

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

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

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

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

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 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

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

Partial agonist activity of the progesterone receptor antagonist RU486 mediated by an amino-terminal domain coactivator and phosphorylation of serine400.

Journal Article Mol Endocrinol · February 2010 Jun dimerization protein-2 (JDP-2) is a progesterone receptor (PR) coregulatory protein that acts by inducing structure and transcriptional activity in the disordered amino-terminal domain (NTD) of PR. JDP-2 can also potentiate the partial agonist activity ... 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

Regulation of the amino-terminal transcription activation domain of progesterone receptor by a cofactor-induced protein folding mechanism.

Journal Article Mol Cell Biol · October 2005 We previously identified a small basic leucine zipper (bZIP) protein, Jun dimerization protein 2 (JDP-2), that acts as a coregulator of the N-terminal transcriptional activation domain of progesterone receptor (PR). We show here that JDP-2, through interac ... Full text Link to item Cite

Mechanisms controlling agonist and antagonist potential of selective progesterone receptor modulators (SPRMs).

Journal Article Semin Reprod Med · February 2005 Progesterone exhibits diverse biological activities, inducing proliferation of the mammary gland epithelium, but it opposes the mitogenic activity of estrogen in the uterus. These tissue-selective activities of progesterone are mediated by the progesterone ... Full text Link to item Cite

Progesterone receptor interacting coregulatory proteins and cross talk with cell signaling pathways.

Conference J Steroid Biochem Mol Biol · December 2002 Progesterone receptor (PR) is a member of the nuclear receptor family of ligand-dependent transcription activators and is expressed as two different sized proteins from a single gene; PR-A and PR-B. The two PR isoforms are identical in their DNA binding do ... Full text Link to item Cite

Jun dimerization protein 2 functions as a progesterone receptor N-terminal domain coactivator.

Journal Article Mol Cell Biol · August 2002 The progesterone receptor (PR) contains two transcription activation function (AF) domains, constitutive AF-1 in the N terminus and AF-2 in the C terminus. AF-2 activity is mediated by a hormone-dependent interaction with a family of steroid receptor coact ... Full text Link to item Cite