Differential roles of androgen receptor in prostate development and cancer progression

The androgen depletion therapy (ADT) has become the major treatment for the cancer patients through the use of chemical castration and/or antiandrogens, yet the therapy eventually fails and cancers progress to more advanced stages. The mutation, amplification, overexpression of AR, and cross-talk between AR, AR co-regulators, and other growth factor pathways have provided potential explanations for the failure of androgen ablation therapies in some cases. However, whether the differential AR roles in different types of prostate cells could contribute to the failure of ADT remains unclear and will be the focus of this review. AR expresses in both stromal and epithelial compartments of prostate. It has been shown that there are three basic types of prostatic epithelial cells: (i) cytokeratin 8 (CK8)-positive, CK5-negative luminal cells, (ii) CK5/CK8-double positive intermediate cells, and (iii) CK8-negative, CK5-positive basal cells. In addition to prostatic stromal cells, AR expression could be detected in some basal cells, some intermediate cells, and all luminal cells in prostate. By Cre-LoxP strategy, the prostate epithelium-specific AR knockout (pes-ARKO) and inducible-cre ARKO mice were recently established and have allowed the field to address the differential and distinct AR roles in different types of prostatic cells. These ARKO mice were bred with TRAMP prostate cancer model, and results from these models suggest that (i) prostatic epithelial AR plays dual roles as a suppressor of basal cell proliferation and as a survival factor for luminal cells, and (ii) the stromal AR plays a proliferator role to support the epithelial cell survival and proliferation. Using microarray analysis of primary tumor cells isolated from the prostate tumors of pes-ARKO-TRAMP mice, it was found that a series of metastatic genes were altered and responsible for the higher invasiveness and metastatic rates. These recent ARKO animal studies not only advance our understanding of the differential roles of AR in different type of prostatic cells, but also closely reflect the pathological changes for the patients undergoing the ADT. Together, these findings provide new evidences to support the potential beneficial effects of intermittent ADT therapy, and they also urge the development of cell type and stage selective anti-AR therapies for the prostate cancer patients.