The Master Neural Transcription Factor BRN2 is an Androgen Receptor Suppressed Driver of Neuroendocrine Differentiation in Prostate Cancer
Mené in vitro et in vivo sur des modéles de cancer neuroendocrine de la prostate, cette étude met en évidence le rôle joué par le facteur de transcription BRN2 dans la croissance rapide des tumeurs
Mechanisms controlling 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 as a major driver of NEPC and aggressive tumor growth, both in vitro and in vivo. Mechanistic studies showed the 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 CRPC compared to adenocarcinoma, especially in patients with low serum PSA. These data reveal a novel mechanism of AR-dependent control of NEPC and suggest targeting BRN2 is a strategy to treat or prevent neuroendocrine differentiation in prostate tumors.