Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation.

Abstract

Master regulatory genes of tissue specification play key roles in stem/progenitor cells and are often important in cancer. In the prostate, androgen receptor (AR) is a master regulator essential for development and tumorigenesis, but its specific functions in prostate stem/progenitor cells have not been elucidated. We have investigated AR function in CARNs (CAstration-Resistant Nkx3.1-expressing cells), a luminal stem/progenitor cell that functions in prostate regeneration. Using genetically--engineered mouse models and novel prostate epithelial cell lines, we find that progenitor properties of CARNs are largely unaffected by AR deletion, apart from decreased proliferation <i>in vivo</i>. Furthermore, AR loss suppresses tumor formation after deletion of the <i>Pten</i> tumor suppressor in CARNs; however, combined <i>Pten</i> deletion and activation of oncogenic <i>Kras</i> in AR-deleted CARNs result in tumors with focal neuroendocrine differentiation. Our findings show that AR modulates specific progenitor properties of CARNs, including their ability to serve as a cell of origin for prostate cancer.