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

Abstract

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.

Emerging Variants of Castration-Resistant Prostate Cancer

“…In addition to the N-myc/PTEN [27], N-myc/AKT [26], and the TP53/RB1 model [36-39] systems that drive NEPC, enzalutamide resistant models [40, 41], patient-derived xenograft (PDX) models [42, 43] and patient-derived organoids [44, 45] may be used to study drug resistance and the development of NEPC [42, 43]. Preclinical observations using these model systems combined with evaluation of additional patient samples have elucidated additional NEPC associated biologic pathways.…”

AR Signaling and the PI3K Pathway in Prostate Cancer

“…Despite initial responses in many however, resistance to these agents is inevitable and remains an intractable problem. Resistance to these therapies may occur broadly through at least three mechanisms [6,10,12,15,24,32,33,34,35]: (1) AR-independent activation of AR-dependent pathways via bypass mechanisms, such as through up-regulation of glucocorticoid receptor expression [32]; (2) De-differentiation such as BRN2-mediated trans-differentiation to neuroendocrine prostate carcinoma [36]; and (3) The most commonly targeted mechanism, direct reactivation of the AR and its signaling despite castrate levels of androgens. The third mechanism can occur via AR gene amplification or AR protein overexpression.…”

A Prominent Couple

“…Recently, INSM1-induced expression of ASCL1, CHGA, NCAM1, SYP, and BRN2 was demonstrated in PCa and lung adenocarcinoma cells. A ChIP-assay revealed ASCL1 promoter binding by INSM1 suggesting INSM1 as direct regulator of a NE program in lung cancer [68,69]. INSM1 recruits cyclin D1 and histone deacetylase 3 (HDAC3) leading to altered histone H3/4 acetylation and reduced promoter activity of target genes [70].…”

“…NE cells containing neurosecretory granules by electron microscopy, are immunohistochemically detected by positive staining for synaptophysin (SYP) (Figure 1.1A), chromogranins A and B (CHGA, CHGB), neuron-specific enolase (NSE/ENO2), or neuronal cell adhesion molecule (NCAM1/CD56) [67] [68]. NEPC is the most significant histological subtype of PCa compared to other rare categories such as ductal adenocarcinoma, mucinous carcinoma, and signet ring carcinoma [69].…”

“…In 2014, the highest incidence rates for PCa in the US were in the age group of [65][66][67][68][69][70][71][72][73][74] years, while between 1975-1995 the incidence rates were in the group of 75 years or older indicating that the diagnosis is currently made at younger age [7]. The incidence rates for PCa are highly variable between different geographical areas, with highest incidence in industrialized countries [6].…”