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The Master Neural Transcription Factor BRN2 Is an Androgen Receptor Suppressed Driver Of Author Manuscript Published OnlineFirst on October 26, 2016; DOI: 10.1158/2159-8290.CD-15-1263 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. The master neural transcription factor BRN2 is an androgen receptor suppressed driver of neuroendocrine differentiation in prostate cancer Jennifer L. Bishop1, Daksh Thaper1,2, Sepideh Vahid1,2, Alastair Davies1, Kirsi Ketola1, Hidetoshi Kuruma1, Randy Jama1, Ka Mun Nip1,2, Arkhjamil Angeles1, Fraser Johnson1, Alexander W. Wyatt1,2, Ladan Fazli1,2, Martin E. Gleave1,2, Dong Lin1, Mark A. Rubin3, Colin C. Collins1,2, Yuzhuo Wang1,2, Himisha Beltran3 and Amina Zoubeidi1,2 1: Vancouver Prostate Centre, Vancouver, BC, CAN. 2: Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver BC, CAN. 3: Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY, USA. Running Title: BRN2 is an androgen-suppressed driver of NEPC Conflict of Interest: The authors have no conflicts of interest to disclose. Corresponding Author Information: Amina Zoubeidi, PhD Associate Professor Vancouver Prostate Centre Department of Urologic Sciences, University of British Columbia [email protected] 2660 Oak Street, Vancouver BC V6H3Z6, CAN 604-875-4818 1 Downloaded from cancerdiscovery.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 26, 2016; DOI: 10.1158/2159-8290.CD-15-1263 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 ABSTRACT 2 Mechanisms controlling emergence of lethal neuroendocrine prostate cancer (NEPC), especially those 3 that are consequences of treatment-induced suppression of the androgen receptor (AR), remain 4 elusive. Using a unique model of AR pathway inhibitor-resistant prostate cancer, we identified AR- 5 dependent control of the neural transcription factor BRN2 as a major driver of NEPC and aggressive 6 tumor growth, both in vitro and in vivo. Mechanistic studies showed the AR directly suppresses BRN2 7 transcription, which is required for NEPC, and BRN2-dependent regulation of the NEPC marker, SOX2. 8 Underscoring its inverse correlation with classic AR activity in clinical samples, BRN2 expression was 9 highest in NEPC tumors and was significantly increased in CRPC compared to adenocarcinoma, 10 especially in patients with low serum PSA. These data reveal a novel mechanism of AR-dependent 11 control of NEPC and suggest targeting BRN2 is a strategy to treat or prevent neuroendocrine 12 differentiation in prostate tumors. 13 14 15 16 17 18 19 20 21 22 23 2 Downloaded from cancerdiscovery.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 26, 2016; DOI: 10.1158/2159-8290.CD-15-1263 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 24 SIGNIFICANCE 25 Understanding the contribution of the androgen receptor (AR) to the emergence of highly lethal, drug 26 resistant neuroendocrine prostate cancer (NEPC) is critical for better implementation of current 27 standard of care therapies and novel drug design. Our first-in-field data underscore the consequences 28 of potent AR inhibition in prostate tumors, revealing a novel mechanism of AR-dependent control of 29 neuroendocrine differentiation and uncover BRN2 as a potential therapeutic target to prevent 30 emergence of NEPC. 31 32 . 33 34 35 36 37 38 39 40 41 42 43 44 3 Downloaded from cancerdiscovery.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 26, 2016; DOI: 10.1158/2159-8290.CD-15-1263 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 45 INTRODUCTION 46 Progression from primary prostate cancer (PCa) to advanced metastatic disease is heavily 47 dependent on the androgen receptor (AR), which fuels tumor survival. In men where treatments for 48 localized prostate tumors have failed, or in those who present with metastatic disease, androgen 49 deprivation therapies (ADT) are used to deplete circulating androgens to abrogate AR signalling and 50 prevent disease progression. Eventually however, PCa recurs after first-line ADT as castration resistant 51 prostate cancer (CRPC). Despite low levels of serum androgens in men with CRPC, reactivation of the 52 AR occurs; thus it remains central to tumor cell survival, proliferation and metastatic spread. Thus, 53 targeting the AR is a cornerstone therapeutic intervention in CRPC patients and AR pathway inhibitors 54 (APIs) that further prevent AR activation, such as enzalutamide (ENZ), have become mainstays in the 55 PCa treatment landscape (1). Despite being a potent API, the treatment benefits of ENZ are short lived 56 in CRPC patients and resistance rapidly occurs (2). 57 ENZ resistant (ENZR) CRPC represents a significant clinical challenge due not only to the lack 58 of third-line treatment options to prevent AR driven tumor progression, but also because it can be a 59 precursor to rapidly progressing and lethal neuroendocrine prostate cancer (NEPC). Although NEPC 60 can rarely arise de-novo, it is increasingly defined as a variant of highly API-resistant CRPC (3,4). 61 Aside from the unique small cell morphology and positive staining for neuroendocrine (NE) markers that 62 characterize NEPC, it is often distinguished from prostatic adenocarcinoma by reduced AR expression 63 or activity (5). Clinical presentation of NEPC reflects this shift away from reliance on the AR, as patients 64 typically present with low circulating levels of prostate specific antigen (PSA) despite high metastatic 65 burden in soft tissues, and are refractory to APIs (3). Importantly, it has been reported that under the 66 strong selective pressure of potent APIs like ENZ, these “non-AR driven” prostate cancers, which 67 include NEPC, may constitute up to 25% of advanced, drug resistant CRPC cases (6). Not surprisingly 68 therefore, the incidence of NEPC has significantly increased in recent years (7), coinciding with the 69 widespread clinical use of APIs. 4 Downloaded from cancerdiscovery.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 26, 2016; DOI: 10.1158/2159-8290.CD-15-1263 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 70 A number of molecular mechanisms likely facilitate the progression of CRPC to NEPC. These 71 include loss of tumor suppressors like RB1 (8,9) and p53 (10), amplification of n-Myc (11), mitotic 72 deregulation through AURKA (11) and PEG10 (12), epigenetic controls such as REST (13-15) and 73 EZH2 (11,16) and splicing factors like SSRM4 (14,17). Importantly, the AR plays a crucial, albeit still 74 mechanistically unclear, role in NEPC. Reports over many years have highlighted how ADT (18,19) or 75 loss of AR promotes the NE differentiation of prostate cancer cells (reviewed in (20))); as such, many 76 genes associated with a NE phenotype, including ARG2 (21), hASH-1 (22) and REST (15,23) are 77 controlled by the AR. Although this evidence underscores an inverse correlation between AR 78 expression and/or activity and molecular events leading to NEPC, the mechanisms by which the AR 79 directly influence the induction of a NEPC phenotype from CRPC under the selective pressure of APIs 80 like ENZ remain elusive. 81 Answering such questions requires a model of API resistant CRPC that recapitulates the trans- 82 differentiation of adenocarcinoma to NEPC that occurs in patients. Herein, we present an in vivo 83 derived model of ENZR, which different to others (24-26), underscores the emergence of tumors with 84 heterogeneous mechanisms of resistance to ENZ over multiple transplanted generations. These 85 include the natural acquisition of known AR mutations found in ENZR patients (26-29) and the 86 transdifferentiation of NEPC-like tumors through an AR+ state, without the manipulation of oncogenes 87 typically used to establish NEPC in murine PCa models (30-32) . Using this model and human PCa 88 patient data, we show that a master regulator of neuronal differentiation, the POU-domain transcription 89 factor BRN2 (POU3F2) (33), is directly transcriptionally repressed by the AR, is required for the 90 expression of terminal NE markers and aggressive growth of ENZR CRPC, and is highly expressed in 91 human NEPC and metastatic CRPC with low circulating PSA. Beyond suppressing BRN2 expression 92 and activity, we also show that the AR inhibits BRN2 regulation of SOX2, another transcription factor 93 associated with NEPC. These results suggest that relief of AR-mediated suppression of BRN2 is a 94 consequence of ENZ treatment in CRPC that may facilitate the progression of NEPC, especially in men 5 Downloaded from cancerdiscovery.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 26, 2016; DOI: 10.1158/2159-8290.CD-15-1263 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 95 with “non-AR driven” disease. 96 RESULTS 97 Emergence of AR-driven and non- driven tumors in ENZR CRPC 98 To model ENZ resistant (ENZR) disease, we developed cell lines from LNCaP-CRPC and ENZR 99 LNCaP-CRPC xenograft tumors. LNCaP cells were used to establish subcutaneous tumors in intact 100 male athymic nude mice and upon tumor growth and rising PSA, mice were castrated. Once tumors 101 recurred (CRPC) mice were treated with vehicle or 10mg/kg ENZ daily and monitored for tumor growth 102 (Fig. S1A, Supplementary Methods). While ENZ treatment did slow tumor growth compared to vehicle 103 control, it did not prevent tumor recurrence (Fig. 1A) and the majority of (9 out of 10, 90%) ENZ treated 104 CRPC tumors increased in tumor volume with concomitant rise in PSA (Fig.
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