androgen deprivation therapy ͉ testosterone ͉ TGF␤1 ͉ metastasis E arly studies suggested that the prostatic epithelial androgen receptor (AR), when activated by androgens, increased cellular proliferation (1, 2). Clinical studies also pointed out that androgen deprivation therapy (ADT) with suppression of androgens/AR functions, is an effective treatment for most prostate cancer patients (3, 4). However, most prostate tumors regrow after 12-18 months of continuous ADT (1-4). The detailed mechanisms of why suppression of androgens/AR ultimately fails and cancers recur as a more aggressive type and metastasize remain unclear.The conventional concept of the AR role in prostate cancer is to promote cancer progression, and positive AR staining can be found in many prostate tumors even at the later stages. In addition to androgens, other factors could also affect AR activity, such as (a) AR mutations or amplification, (b) changes in AR and AR coregulators interactions, or (c) growth factors/kinases signal pathways that activate AR activity at the castration level of androgen (1-4). However, why patients receiving ADT tended to have an earlier development of more aggressive types of cancer and whether AR has a differential role in different prostatic cells and/or in different prostate cancer stages remain unclear.Here, we report the generation of a mouse cancer model lacking the AR only in its prostatic epithelium (pes-ARKO-TRAMP), which develops prostate cancer spontaneously with an intact immune system. Notably, through AR gain-and loss-of-function in epithelial-stromal cell coculture and coimplantation experiments, we demonstrated that the AR could function in epithelial basal intermediate cells as a tumor suppressor to suppress prostate cancer metastasis, in epithelial luminal cells as a surviving factor, and in stromal cells as a proliferator to stimulate cancer progression. These contrasting data challenge the currently used ADT that systematically suppresses androgen actions, and thus reduces both proliferative and suppressor functions of AR. Our results suggest the need for better therapies that only target the proliferative function of AR.

Developmental studies of the prostate have established that ductal morphogenesis, epithelial cytodifferentiation, and proliferation/apoptosis are regulated by androgens acting through stromal androgen receptor (AR). Here, we found mice lacking epithelial AR within the mature prostate (pes-ARKO) developed prostate tissue that was less differentiated and hyperproliferative relative to WT littermates. Epithelial AR protein was significantly decreased in 6-week-old mice and was nearly absent by ≥24 weeks of age. Circulating levels of testosterone, external genitalia, or fertility were not altered in pes-ARKO mice. A significant ( P < 0.05) increase in bromo-deoxyuridine-positive epithelia was observed in ventral and dorsal-lateral prostates of pes-ARKO mice at 24 weeks of age. Less differentiation was observed as indicated by decreased epithelial height and glandular infolding through 24 weeks of age, differentiation markers probasin, PSP-94, and Nkx3.1 were sig nificantly decreased, and epithelial sloughing and luminal cell apoptosis increased from 6 to 32 weeks of age in pes-ARKO mice. Gain of function occurred by crossing pes-ARKO to the T857A transgenic mice containing constitutively activated AR. In T857A-pes-ARKO mice prostates were of normal size, contained glandular infoldings, and maintained high secretory epithelium, and the appropriate prostatic epithelial proliferation was restored. Collectively, these results suggest that prostatic epithelial AR plays an important role in the homeostasis of the prostate gland. These data support the hypothesis that epithelial AR controls prostate growth by suppressing epithelial proliferation in the mature gland.

To differentiate roles of androgen receptor (AR) in prostate stromal and epithelial cells, we have generated inducible-(ind)ARKO-TRAMP and prostate epithelial-specific ARKO TRAMP (pes-ARKO-TRAMP) mouse models, in which the AR was knocked down in both prostate epithelium and stroma or was knocked out in the prostate epithelium, respectively. We found that loss of AR in both mouse models resulted in poorly differentiated androgen deprivation therapy ͉ testosterone ͉ TRAMP