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Androgen is the major growth and survival factor for the prostate that functions by regulating the paracrine interaction between the stromal and epithelial compartments of the prostate. In prostatic stromal cells, androgen engages androgen receptor (AR), which activates the synthesis and secretion of peptide growth and survival factors known as andromedins. These andromedins diffuse into the basal layer of the epithelial compartment, where they bind to their cognate receptors in AR-negative transit-amplifying (TA) cells inducing the appropriate signaling pathways to promote survival and proliferation of these cells. These TA cells arise from the epithelial stem cells and are the major subset of proliferating epithelial cells within the prostate. Normally, these TA cells proliferate within the basal layer and subsequently their progeny mature into intermediate cells (IC). These IC migrate into the luminal layer where they now express AR and the ligand occupancy of the AR, terminally differentiates the IC cells into secretory luminal cells, which express prostate specific differentiation markers like PSA. Using dual immunohistochemical staining for the AR and the cell cycle marker, Ki67, proliferating (i.e., nuclear Ki67 positive) normal TA cells were documented to have low to undetectable AR expression, while proliferatively quiescent secretory luminal cells were nuclear AR positive and Ki67 negative. This observation suggested that ligand occupied AR might be functioning as a tumor suppressor of normal prostatic epithelial growth. To test this hypothesis, early passage normal prostatic epithelial cells (i.e., PrEC) and hTERT immortalized TA cells (i.e., 957 E/hTERT) were documented to be negative for AR expression and, hence, were transduced with a lentiviral construct containing AR gene with the proper regulatory full-length 5‘UTR and partial 3‘UTR. We documented that within these transduced cells AR protein was expressed by Western Blot, was functional by its ability to drive the expression of luciferase reporter from an AR-sensitive promoter and by immunocytochemistry we documented that AR localized to the nucleus upon exposure to synthetic androgen, R1881. In these normal prostate cells, AR significantly inhibited cell growth in the presence of 1 nM of R1881. Furthermore, cells that continued to grow in the presence of androgen no longer expressed AR, as documented by immunocytochemistry. The observed growth inhibition correlated well with the enhanced expression of p21, a cell-cycle inhibitor.We have previously reported that during prostatic carcinogenesis, there is a conversion in the androgen axis from stromal-cell-dependent paracrine signaling to autocrine pathway in which occupancy of AR within the cancer cells themselves directly stimulates their survival and proliferation. Such a conversion involves molecular changes that shift AR from tumor suppressor to an oncogene.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]