Dissecting cell-type-specific roles of androgen receptor in prostate homeostasis and regeneration through lineage tracing

Qing Xie,Yueli Liu,Tao Cai,Zhu A Wang,Joshua Stefanson,Corrigan Horton

doi:10.1038/ncomms14284

Abstract

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.

Highlights

Androgen signals through androgen receptor (AR) to influence prostate development and cancer
Our immunofluorescence (IF) staining of adult mouse prostate confirmed strong nuclear AR expression in all luminal cells (Fig. 1a), and interestingly, revealed its expression to be heterogeneous in the basal layer, as strong AR nuclear staining was randomly present in a subset of basal cells (Fig. 1a)
We found basal AR deletion to be efficient but not fully penetrant, as the percentage of YFP þ basal cells that were AR þ significantly decreased to 22.2% in the anterior prostate (AP) lobes 2 weeks after induction

Summary

Introduction

Androgen signals through androgen receptor (AR) to influence prostate development and cancer. The function of AR in the adult prostate epithelium, at the resolution of specific adult epithelial cell types, remains unclear Acquiring such knowledge will be crucial for our understanding of prostate homeostasis and cancer initiation. Deletion of the tumour suppressor gene Pten in the mouse prostate epithelium has served as a highly relevant model for studying human prostate cancer[26] Under this oncogenic condition, basal, luminal and CARN cells all can serve as the cell of origin for prostate cancer[19,20,23,27]. Through cell-type-specific ablation of AR coupled with lineage-tracing analyses, our data demonstrate distinct AR functions in adult basal and luminal cells, and uncover its essential roles in the multipotent capability of rare stem cells in both compartments

Methods

Results

Conclusion