) The human prostate is androgen dependent and prostate cancer (CaP), maintains this dependence on androgens. CaP undergoes apoptosis and regression following androgen withdrawal but eventually recurs in the absence of testicular androgens. The human CaP xenograft (CWR22) propagated in male nude mice, retains these biological characteristics including regression following castration and recurrence of growth after several months in the absence of testicular androgen. Following the withdrawal of androgen stimulation, AR levels decrease in CWR22. However, recurrent CWR22 tumors express high levels of AR relative to the regressing CWR22 from castrated mice. In recurrent CWR22 the increased intensity of nuclear immunostaining is consistent with AR activation in the absence of androgen. Moreover, androgen-regulated mRNAs that decrease in CWR22 tumors following castration are up-regulated in the recurrent XWR22. The goal of this research is to establish the role of AR and the AR target gene network in the androgen-independent growth of CaP.
Specific Aims of this project are to: (1) Delineate the mechanisms controlling steady state expression levels of AR mRNA and protein in CWR 22 tumors after castration and recurrent growth. Characterize the activation properties of AR (protein stability and phosphorylation) in recurrent CWR22 tumors. (2) Identify androgen-regulated genes in CWR22 with emphasis on potential mediators of AR-stimulated cell growth. Compare the levels of expression of these androgen-regulated genes in CWR22 with emphasis on potential mediators of AR-stimulated cell growth. Compare the levels of expression of these androgen- regulated genes in castrate mice. (3) Determine the androgen-independent function of AR in the recurrent CWR22 tumors using a dominant- negative AR to inhibit AR to inhibit AR transactivation and an AR- directed ribozyme to prevent AR expression. (4) Elucidate the mechanism controlling expression of androgen-regulated genes in the recurrent CWR22 (a) AR-dependent mechanism; or (b) non-AR dependent mechanism.
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