title: The Master Neural Transcription Factor BRN2 Is an Androgen Receptor-Suppressed Driver of Neuroendocrine Differentiation in Prostate Cancer.
abstract: Mechanisms controlling the emergence of lethal neuroendocrine prostate cancer (NEPC), especially those that are consequences of treatment-induced suppression of the androgen receptor (AR), remain elusive. Using a unique model of AR pathway inhibitor-resistant prostate cancer, we identified AR-dependent control of the neural transcription factor BRN2 (encoded by POU3F2) as a major driver of NEPC and aggressive tumor growth, both in vitro and in vivo Mechanistic studies showed that AR directly suppresses BRN2 transcription, which is required for NEPC, and BRN2-dependent regulation of the NEPC marker SOX2. Underscoring its inverse correlation with classic AR activity in clinical samples, BRN2 expression was highest in NEPC tumors and was significantly increased in castration-resistant prostate cancer compared with adenocarcinoma, especially in patients with low serum PSA. These data reveal a novel mechanism of AR-dependent control of NEPC and suggest that targeting BRN2 is a strategy to treat or prevent neuroendocrine differentiation in prostate tumors.
  
  
  
  Understanding the contribution of the AR to the emergence of highly lethal, drug-resistant NEPC is critical for better implementation of current standard-of-care therapies and novel drug design. Our first-in-field data underscore the consequences of potent AR inhibition in prostate tumors, revealing a novel mechanism of AR-dependent control of neuroendocrine differentiation, and uncover BRN2 as a potential therapeutic target to prevent emergence of NEPC. Cancer Discov; 7(1); 54-71. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors: Jennifer L
authors: JL
authors: Bishop
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Daksh
authors: D
authors: Thaper
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Sepideh
authors: S
authors: Vahid
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors: Alastair
authors: A
authors: Davies
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors: Kirsi
authors: K
authors: Ketola
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors: Hidetoshi
authors: H
authors: Kuruma
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors: Randy
authors: R
authors: Jama
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Ka Mun
authors: KM
authors: Nip
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors: Arkhjamil
authors: A
authors: Angeles
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors: Fraser
authors: F
authors: Johnson
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Alexander W
authors: AW
authors: Wyatt
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Ladan
authors: L
authors: Fazli
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Martin E
authors: ME
authors: Gleave
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors: Dong
authors: D
authors: Lin
authors: Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York.
authors: Mark A
authors: MA
authors: Rubin
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Colin C
authors: CC
authors: Collins
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Yuzhuo
authors: Y
authors: Wang
authors: Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York.
authors: Himisha
authors: H
authors: Beltran
authors: Vancouver Prostate Centre, Vancouver, British Columbia, Canada. azoubeidi@prostatecentre.com.|Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Amina
authors: A
authors: Zoubeidi
mesh_terms: D000818:Animals; D001549:Benzamides; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009570:Nitriles; D050809:POU Domain Factors / Q000235:genetics* / Q000378:metabolism; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: C410798:AR protein, human; D001549:Benzamides; D018398:Homeodomain Proteins; D009570:Nitriles; D050809:POU Domain Factors; D011944:Receptors, Androgen; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C085076:transcription factor Brn-2; D010669:Phenylthiohydantoin; C540278:enzalutamide