Ongoing research in this POI has contributed significantly to the concept that androgen receptor (AR) signaling is essential to the recurrence of prostate cancer (CaP) during androgen deprivation. First, it was discovered that tissue androgen levels in recurrent CaP are sufficient for AR stimulation of growth, and that blocking AR function inhibits growth. These observations are well supported by recent clinical trials showing that recurrent CaP responds to treatment with a steroidogenic enzyme inhibitor that blocks the synthesis of androgens in CaP tissue. Second, with the discovery of MAGE-11, major progress has been made towards understanding AR stimulation of cell proliferation. MAGE-11, an AR coregulator overexpressed in recurrent CaP, links AR to cell growth through interactions with key cell cycle regulatory proteins and tumor suppressors. Initial studies indicate that MAGE-11 is vital to AR stimulation of cell proliferation. Third, AR was identified in endothelial cells of the prostate microvasculature. A unique human prostate xenograft model that utilizes fresh tissue from radical prostatectomy specimens has been developed that allows for the study of AR action in the prostate microvasculature, and the regulation of androgen transport across the endothelial barrier. The unifying hypothesis of this POI application is that advanced CaP can be treated more effectively by androgen deprivation therapy combined with new strategies that target the AR. Project 1 will pursue the elimination ofAR transcriptional activity during the post-castration period using strategies that prevent the synthesis of androgen, cause the degradation of AR ligands or their precursors and/or eliminate AR function. Project 2 will characterize MAGE-11 as a target for inhibition of AR-stimulated cell growth. It will establish the cell cycle dependence of MAGE-11 expression and the effect of MAGE-11 knockdown on cell proliferation, identify the adenovirus EIA-Iike properties of MAGE-11 that inactivate the retinoblastoma pocket proteins, Rb and p107, and determine the influence of MAGE-11 and Rb/p107 on Skp2 stimulation of cell proliferation through the degradation of the p27-Kip1 tumor suppressor. Project 3 will determine the effects of androgen deprivation on endothelial cell functions ofthe prostate microvasculature including androgen endocytosis, metabolism and transport, identify aberrant functions of HNF-4a in CaP stem cells, and target CaP stem cells using strategies related to perturbation of the endothelial steroid barrier during androgen deprivation therapy.
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