): Prostate cancer is the second leading cause of cancer-related death in American men. Androgen-independent metastasis is the principal cause of death among patients with prostate cancer. The applicants have recently established an androgen-dependent human prostate cancer xenograft. Consistent with the clinical course of human prostate cancer, xenograft tumors regress after hormonal ablation, then progress to become androgen-independent. Androgen-independent sublines have been derived and passaged in castrate mice. Representational Difference Analysis (RDA), a PCR-based subtractive cloning strategy, was used to identify a number of genes unregulated in androgen-independent xenograft sublines. These genes include human renal kallikrein, a secreted serine protease, and human E25, a novel Type II membrane protein. The goal of this proposal is to use RDA to identify additional cell surface and intercellular signaling molecules whose expression or loss of expression is specific for androgen-independent prostate cancer. Differential expression of candidate genes will be correlated with patient samples of androgen-dependent and independent prostate cancer. Full length cDNAs of genes confirmed to be differentially expressed will be cloned. Genes of interest will be tested functionally for their ability to alter the biological behavior o f a n d rogen-dependent and independent prostate cancer cell lines. Identification and characterization of these molecules will lead to the development of new diagnostic and therapeutic strategies for androgen refractory metastatic prostate cancer.
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