The long-term goals are to develop effective modulations for preventing cancer progression, and treating hormone-refractory cancers. In this proposal, the molecular mechanism of androgen-refractory growth of prostate cancer cells will be delineated. Preliminary data show that the signaling from ErbB-2, via the mitogen-activated protein kinase (MAPK) pathway including p52Shc and p42MAPK, plays a critical role in androgen action of cell growth. Further, the pMAPK level is elevated in some hormone-refractory human archival specimens. Thus, the working hypothesis is that the increased tyrosine phosphorylation signaling by ErbB-2, due to decreased expression of cellular prostate acid phosphatase (cPAcP), plays a critical role in prostate cancer progression, leading to the hormone-refractory growth. The altered regulatory molecules involving in the androgen-refractory growth may serve as biomarkers for tumor progression, and as targets for therapy.
The specific aims are: (1) to transfect androgen-responsive cells with a cDNA encoding ErbB-2. It will be tested if an increased ErbB-2 activity can lead to the hormone-refractory growth. The ErbB-2 activity will then be suppressed by transfecting those same cells with a dominant negative regulator of ErbB-2 cDNA for examining the effect of decreased ErbB-2 activity on the androgen responsiveness; (2) to ectopically express a dominant negative regulator of PAcP by cDNA transfection in androgen-responsive, PAcP-expressing prostate cells. The effect of loss of cPAcP activity on androgen stimulation will be examined; (3) to transfect cells with a cDNA encoding a wild type p52Shc or its dominant negative regulator. The effect of altered Shc activity on androgen responsiveness will be examined; (4) to quantify the MAPK activity in androgen-responsive and unresponsive cells. The functional role of p42MAPK in androgen-refractory growth and androgen regulation of prostate-specific antigen expression will be delineated. Androgen effect on the MAPK activity will also be examined; (5) to analyze if ErbB-2 and MAPK have elevated activities in androgen-refractory human prostate carcinoma archival specimens by immunohistochemical staining with specific Abs. The in vitro findings will be correlated with the morphological progression of clinical tumors.
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