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Cancer Discov. 2017 Jan;7(1):54-71. doi: 10.1158/2159-8290.CD-15-1263. Epub 2016 Oct 26.

The Master Neural Transcription Factor BRN2 Is an Androgen Receptor-Suppressed Driver of Neuroendocrine Differentiation in Prostate Cancer.

Author information

1
Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
2
Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
3
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York.
4
Vancouver Prostate Centre, Vancouver, British Columbia, Canada. azoubeidi@prostatecentre.com.

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.

SIGNIFICANCE:

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.

PMID:
27784708
DOI:
10.1158/2159-8290.CD-15-1263
[Indexed for MEDLINE]
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