Androgen is an important steroid hormone regulating prostate physiology, and its signal through the androgen receptor (AR) plays critical roles in prostate development and cancer progression. It has been shown that prostate stromal AR and epithelial AR have different functions in organogenesis. Yet the role of epithelial AR in prostate homeostasis and cancer initiation remains controversial. Recent studies have provided a clearer picture of the cell lineage relationships in the prostate epithelium, but how AR regulates them is unclear.
Here, using genetic lineage tracing, we carefully investigated the role of AR in different epithelial cell types of the adult prostate. We show that AR has a heterogeneous expression pattern in adult basal cells, and is dispensable for basal cell maintenance. However, AR is cell-autonomously required for the luminal differentiation capability of rare basal stem cells in vivo. In contrast, AR loss in luminal cells induces a brief period of cell proliferation and disrupts their normal columnar cell morphology and polarity, but it does not affect luminal cell survival or androgen-mediated regression-regeneration. Interestingly, we find that during regeneration AR is selectively required for the multipotency of castration-resistant Nkx3-1-expressing luminal stem cells (CARNs), as it prevents their differentiated daughter cells from apoptosis. Finally, we show that PTEN loss can override AR-loss defects in both basal and luminal compartments to initiate prostate tumors. Our data reveal the multifaceted roles of AR in different prostate epithelial cell types for orchestrating tissue homeostasis in vivo, and highlight the distinct mechanisms utilized by AR in rare basal and luminal stem cells. Our results also argue for a less prominent role of epithelial AR in early prostate cancer initiation.