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Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer.

Publication ,  Journal Article
Stoyanova, T; Riedinger, M; Lin, S; Faltermeier, CM; Smith, BA; Zhang, KX; Going, CC; Goldstein, AS; Lee, JK; Drake, JM; Rice, MA; Hsu, E-C ...
Published in: Proc Natl Acad Sci U S A
October 18, 2016

Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer.

Duke Scholars

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

October 18, 2016

Volume

113

Issue

42

Start / End Page

E6457 / E6466

Location

United States

Related Subject Headings

  • ras Proteins
  • raf Kinases
  • Tumor Burden
  • Signal Transduction
  • Receptor, Notch1
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins c-akt
  • Prostatic Neoplasms, Castration-Resistant
  • Phenotype
  • Neoplasm Metastasis
 

Citation

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Stoyanova, T., Riedinger, M., Lin, S., Faltermeier, C. M., Smith, B. A., Zhang, K. X., … Witte, O. N. (2016). Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer. Proc Natl Acad Sci U S A, 113(42), E6457–E6466. https://doi.org/10.1073/pnas.1614529113
Stoyanova, Tanya, Mireille Riedinger, Shu Lin, Claire M. Faltermeier, Bryan A. Smith, Kelvin X. Zhang, Catherine C. Going, et al. “Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer.Proc Natl Acad Sci U S A 113, no. 42 (October 18, 2016): E6457–66. https://doi.org/10.1073/pnas.1614529113.
Stoyanova T, Riedinger M, Lin S, Faltermeier CM, Smith BA, Zhang KX, et al. Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer. Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):E6457–66.
Stoyanova, Tanya, et al. “Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer.Proc Natl Acad Sci U S A, vol. 113, no. 42, Oct. 2016, pp. E6457–66. Pubmed, doi:10.1073/pnas.1614529113.
Stoyanova T, Riedinger M, Lin S, Faltermeier CM, Smith BA, Zhang KX, Going CC, Goldstein AS, Lee JK, Drake JM, Rice MA, Hsu E-C, Nowroozizadeh B, Castor B, Orellana SY, Blum SM, Cheng D, Pienta KJ, Reiter RE, Pitteri SJ, Huang J, Witte ON. Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer. Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):E6457–E6466.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

October 18, 2016

Volume

113

Issue

42

Start / End Page

E6457 / E6466

Location

United States

Related Subject Headings

  • ras Proteins
  • raf Kinases
  • Tumor Burden
  • Signal Transduction
  • Receptor, Notch1
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins c-akt
  • Prostatic Neoplasms, Castration-Resistant
  • Phenotype
  • Neoplasm Metastasis