Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, California 95064, USA.
Sequencing Center, National Institute of Biological Sciences, Beijing 102206, China.
Nat Commun. 2017 Jan 23;8:14284. doi: 10.1038/ncomms14284.
Androgen signals through androgen receptor (AR) to influence prostate development and cancer. How stromal and epithelial AR regulate prostate homeostasis remains unclear. Using genetic lineage tracing, we systematically investigated the role of cell-autonomous AR in different prostate epithelial cell types. Here we show that AR is dispensable for basal cell maintenance, but is cell-autonomously required for the luminal differentiation of rare basal stem cells. In contrast, AR deletion in luminal cells alters cell morphology and induces transient over-proliferation, without affecting androgen-mediated luminal cell survival or regeneration. However, AR is selectively required for the maintenance of daughter cells produced by castration-resistant Nkx3.1-expressing luminal stem cells (CARNs). Notably, Pten loss can override AR-loss effects in both basal and luminal compartments to initiate tumours. Our data reveal distinct cell-type-specific roles of epithelial AR in orchestrating prostate homeostasis, and question the notion that epithelial AR serves as a tumour suppressor in early cancer initiation.
雄激素通过雄激素受体 (AR) 发挥信号作用，影响前列腺的发育和癌变。目前尚不清楚基质和上皮 AR 如何调节前列腺的稳态。我们利用遗传谱系追踪技术，系统地研究了 AR 在不同前列腺上皮细胞类型中的作用。结果表明，AR 对于基底细胞的维持是可有可无的，但对于罕见的基底干细胞的管腔分化，AR 是自主需要的。相比之下，管腔细胞中的 AR 缺失会改变细胞形态并诱导短暂的过度增殖，而不会影响雄激素介导的管腔细胞存活或再生。然而，AR 对于由 Nkx3.1 表达的管腔干细胞（CARNs）产生的子细胞的维持是选择性需要的。值得注意的是，Pten 的缺失可以克服基底和管腔中 AR 缺失的影响，从而引发肿瘤。我们的数据揭示了上皮 AR 在协调前列腺稳态方面的独特的细胞类型特异性作用，并对上皮 AR 在早期癌症发生中作为肿瘤抑制因子的观点提出了质疑。
