Proliferative disease of the prostate such as benign prostatic enlargement and prostate cancer are serious health problems in the United States. Prostate adenocarcinoma is now the second leading cause of cancer death among American men. The molecular mechanisms of benign and malignant prostate growth and the process by which malignant cells become androgen-independent during prostate cancer progression have not been elucidated. The experiments outlined in this proposal will test the hypothesis that two recently-discovered members of the EGF family, amphiregulin and heparin-binding EGF-like growth factor (HB-EGF) are physiologic regulators of prostate cell function. We have demonstrated that amphiregulin and HB-EGF are expressed by prostatic epithelial cells and that their expression may be abnormally regulated at multiple levels (mRNA expression, stability and processing; protein expression; and regulation by protein kinase C) as a result of malignant change. Our data suggest that both HB-EGF and amphiregulin may be important, and heretofore unrecognized, mediators of prostate cell growth and potentially of other processes relevant to prostatic physiology and disease.
The specific aims are: (1) To identify the biologically active forms, relative expression levels and sites of cellular localization of amphiregulin and HB-EGF expressed by normal and transformed human and rat prostate epithelial and stromal cells; (2) To characterized the biological effects of amphiregulin and HB-EGF on prostatic cells and to identify sites of cellular synthesis and localizating; (3) To genetically alter amphireguli and HB-EGF expression in prostatic cells to test the following hypotheses: (i) Amphiregulin or HB-EGF expression is necessary for the formation of functional epithelial monolayers and prostatic epithelial cells which lose cell-surface expression of these factors exhibit enhanced malignant properties; (ii) Overexpression of amphiregulin or HB-EGF in transformed prostatic epithelial cells alters malignant properties such as tumor growth in vivo and tumor cell invasion in vitro; (iii) Cytokines implicated in prostate cancer progression activate and release amphiregulin or HB-EGF from epithelial cell surfaces; (iv) Barrier-forming prostatic epithelial cells sequester and release amphiregulin or HB-EGF from epithelial cell sequester and release amphiregulin or HB-EGF in a polarized fashion; and (v) Expression of proAR or proHB-EGF in a human metastatic prostate adenocarcinoma cell can suppress metastasis in vivo.
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