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

Tanya Stoyanova, Mireille Riedinger, Shu Lin, Claire M. Faltermeier, Bryan A. Smith, Kelvin X. Zhang, Catherine C. Going, Andrew S. Goldstein, John K. Lee, Justin M. Drake, Meghan A. Rice, En Chi Hsu, Behdokht Nowroozizadeh, Brandon Castor, Sandra Y. Orellana, Steven M. Blum, Donghui Cheng, Kenneth Pienta, Robert E. Reiter, Sharon J. PitteriJiaoti Huang, Owen N. Witte

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E6457-E6466
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number42
DOIs
StatePublished - Oct 18 2016

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Castration
Prostatic Neoplasms
Prostate
Neoplasms
Epithelial-Mesenchymal Transition
Androgens
Adenocarcinoma
Recurrence
Mortality

Keywords

  • Cancer
  • Notch1
  • Prostate

ASJC Scopus subject areas

  • General

Cite this

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer. / Stoyanova, Tanya; Riedinger, Mireille; Lin, Shu; Faltermeier, Claire M.; Smith, Bryan A.; Zhang, Kelvin X.; Going, Catherine C.; Goldstein, Andrew S.; Lee, John K.; Drake, Justin M.; Rice, Meghan A.; Hsu, En Chi; Nowroozizadeh, Behdokht; Castor, Brandon; Orellana, Sandra Y.; Blum, Steven M.; Cheng, Donghui; Pienta, Kenneth; Reiter, Robert E.; Pitteri, Sharon J.; Huang, Jiaoti; Witte, Owen N.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 42, 18.10.2016, p. E6457-E6466.

Research output: Contribution to journalArticle

Stoyanova, T, Riedinger, M, Lin, S, Faltermeier, CM, Smith, BA, Zhang, KX, Going, CC, Goldstein, AS, Lee, JK, Drake, JM, Rice, MA, Hsu, EC, Nowroozizadeh, B, Castor, B, Orellana, SY, Blum, SM, Cheng, D, Pienta, K, Reiter, RE, Pitteri, SJ, Huang, J & Witte, ON 2016, 'Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 42, pp. E6457-E6466. https://doi.org/10.1073/pnas.1614529113
Stoyanova, Tanya ; Riedinger, Mireille ; Lin, Shu ; Faltermeier, Claire M. ; Smith, Bryan A. ; Zhang, Kelvin X. ; Going, Catherine C. ; Goldstein, Andrew S. ; Lee, John K. ; Drake, Justin M. ; Rice, Meghan A. ; Hsu, En Chi ; Nowroozizadeh, Behdokht ; Castor, Brandon ; Orellana, Sandra Y. ; Blum, Steven M. ; Cheng, Donghui ; Pienta, Kenneth ; Reiter, Robert E. ; Pitteri, Sharon J. ; Huang, Jiaoti ; Witte, Owen N. / Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 42. pp. E6457-E6466.
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AU - Castor, Brandon

AU - Orellana, Sandra Y.

AU - Blum, Steven M.

AU - Cheng, Donghui

AU - Pienta, Kenneth

AU - Reiter, Robert E.

AU - Pitteri, Sharon J.

AU - Huang, Jiaoti

AU - Witte, Owen N.

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N2 - 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.

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