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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • October 18, 2016

Published In

Volume / Issue

  • 113 / 42

Start / End Page

  • E6457 - E6466

PubMed ID

  • 27694579

Pubmed Central ID

  • 27694579

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1614529113

Language

  • eng

Conference Location

  • United States