The androgen receptor (AR) plays key roles in the development of prostate tissue and the development and progression of prostate cancer (PC). AR guides cytodifferentiation and homeostasis in benign luminal epithelial cells; however, in PC, AR instead drives the uncontrolled proliferation of these cells. This 'AR malignancy shift' (AMS) is a central event in tumorigenesis. Using a ChIP-seq approach in primary human tissues, cell lines, and mouse models, we demonstrate that the AMS occurs in every sample analyzed, suggesting that it is necessary for PC development. Using molecular and genetic techniques, we demonstrate that forkhead box (FOX)A1, HOXB13, GATA2, and c-JUN are involved in the regulation of the AMS. AR-binding sites (ARBS) are enriched for FOX, HOX, and GATA motifs in PC cells but not for c-JUN motifs in benign cells. We show that the SPOP mutation commonly found in localized PCs can cause the AMS but is not transformative on its own and must be coupled to another mutation to transform cells. We show that the AMS occurs in mouse models of PC as well and that chronic low T, which is associated with increased PC risk and aggressiveness in humans, also causes the AMS in mice. We have discovered a previously unrecognized, fundamental tenet of PC, one which explains how and why AR signaling is different in cancer and benign cells. Our work has the potential to be used to stratify patients with localized PC for specific treatments. Furthermore, our work suggests that the AMS is a novel target for the treatment and/or prevention of PC.

中文翻译：

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影响良性和恶性前列腺细胞中雄激素受体cistrome的因素。

雄激素受体 (AR) 在前列腺组织的发育和前列腺癌 (PC) 的发生发展中起关键作用。AR 指导良性管腔上皮细胞的细胞分化和稳态；然而，在 PC 中，AR 反而会驱动这些细胞不受控制的增殖。这种“AR 恶性肿瘤转移”(AMS) 是肿瘤发生的核心事件。在原代人体组织、细胞系和小鼠模型中使用 ChIP-seq 方法，我们证明 AMS 出现在分析的每个样本中，表明它对于 PC 开发是必要的。使用分子和遗传技术，我们证明叉头盒 (FOX) A1、HOXB13、GATA2 和 c-JUN 参与了 AMS 的调节。AR 结合位点 (ARBS) 富含 PC 细胞中的 FOX、HOX 和 GATA 基序，但不富含良性细胞中的 c-JUN 基序。我们表明，在局部 PC 中常见的 SPOP 突变会导致 AMS，但它本身不会发生转化，必须与另一个突变结合才能转化细胞。我们表明 AMS 也发生在 PC 的小鼠模型中，并且与人类 PC 风险和攻击性增加相关的慢性低 T 也会导致小鼠发生 AMS。我们发现了一个以前未被认识的 PC 基本原理，它解释了 AR 信号在癌症和良性细胞中如何以及为什么不同。我们的工作有可能用于对局部 PC 患者进行分层以进行特定治疗。此外，我们的工作表明 AMS 是治疗和/或预防 PC 的新目标。