A major obstacle in the treatment of prostate cancer is the development of androgen-independent disease.One of the underlying causes of androgen-independent disease is the up regulation of AR expression, however, the mechanism ofAR gene regulation in androgen-independent cancer is not well understood.We have recently shown that Lefl, a transcription factor activated by WNT signaling, induced expression of the AR gene in androgen-independent prostate cancer cell line, and consequently enhanced cell proliferation and invasion.This suggests that inhibition Lef1 by blocking WNT signaling may represent a new therapeutic approach in combating androgen-independent prostate cancer.While the majority of studies on AR focus on its action in epithelial cells, we are also examining the function of AR in prostate stromal cells.We have shown, using an epithelial-stromal cell coculture system, that AR expression in stromal cells inhibits prostate epithelial cell growth and invasion.We also found that androgen ablation prevented AR in the stroma from suppressing epithelial growth and invasion.Therefore,the lack of stromal AR signaling may, in turn, facilitate the survival, growth, and invasion of a sub-population of the epithelial prostate cancer cells, eventually leading to androgen-independence.In addition to changes in AR expression, alterations in the level or splicing ofAR coactivators could also contribute to androgen-independent prostate cancer cell proliferation.In fact, our lab has found that the AR coactivator ARA70α functions as a tumor suppressor gene in prostate cancer cells.Specifically, the interaction between AR and ARA70α leads to prostate cancer cell apoptosis.The expressionand function of other AR coactivators such as p44/MEP50 and TBLR1 will also be presented.Taken together, our findings lend new insights into the development of androgen-independent prostate cancer and could lead to the development of novel therapies against the disease.