大多数前列腺癌表达雄激素受体（AR），极低水平的全身或肿瘤内产生的雄激素促进肿瘤生长和进展。因此，雄激素信号轴的绝对抑制仍然是当前治疗前列腺癌（PCa）的方法的目标。矛盾的是，高剂量雄激素作为晚期转移性前列腺癌患者的治疗方式也表现出相当大的疗效。在这里，我们发现低水平的雄激素通过 AR 单体发挥作用，促进 mTOR 信号通路的非基因组激活以驱动增殖。相反，高剂量雄激素促进 AR 二聚体/寡聚体的形成，从而抑制 c-MYC 表达、抑制增殖并驱动与分化表型相关的转录程序。这些发现强调了当前用于抑制 PCa 中 AR 作用的方法的固有缺陷，并且对于可用于开发针对这种疾病和其他雄激素病的新疗法的策略具有指导意义。© 2024。作者。

Most prostate cancers express the androgen receptor (AR), and tumor growth and progression are facilitated by exceptionally low levels of systemic or intratumorally produced androgens. Thus, absolute inhibition of the androgen signaling axis remains the goal of current therapeutic approaches to treat prostate cancer (PCa). Paradoxically, high dose androgens also exhibit considerable efficacy as a treatment modality in patients with late-stage metastatic PCa. Here we show that low levels of androgens, functioning through an AR monomer, facilitate a non-genomic activation of the mTOR signaling pathway to drive proliferation. Conversely, high dose androgens facilitate the formation of AR dimers/oligomers to suppress c-MYC expression, inhibit proliferation and drive a transcriptional program associated with a differentiated phenotype. These findings highlight the inherent liabilities in current approaches used to inhibit AR action in PCa and are instructive as to strategies that can be used to develop new therapeutics for this disease and other androgenopathies.© 2024. The Author(s).