The high level of mortality from prostate cancer results from the inexorable growth of overt or occult metastases that ultimately manifest as androgen resistant disease. To better understand the metastatic phenotype in prostate cancer, he developed a strategy to identify mRNAs that are expressed differentially in cell lines derived from primary versus metastatic mouse prostate cancer using differential display-PCR. In using this system, a number of metastasis-related genes were identified including a cDNA that encodes caveolin-1. Caveolin-1 was found to be overexpressed not only in metastatic mouse prostate cancer, but also in human metastatic disease and was shown to be an independent predictor of recurrent following radical prostatectomy. Suppression of caveolin-1 expression induces androgen sensitivity in high caveolin-1, androgen-insensitive mouse prostate cancer cells derived from metastases. Conversely, overexpression of caveolin-1 leads to androgen instensitivity in low caveolin-1 androgen-sensitive mouse prostate cancer cells. He demonstrate that testosterone induces caveolin-1 expression through transcriptional regulation, and that caveolin-1 is a downstream effector for testosterone-induced survival in mouse prostate cancer cells in vitro. He has confirmed in human prostate cancer specimens that caveolin-1 expression is significantly increased in both primary tumors and their metastases following chemical and surgical androgen ablation, and preliminary studies suggest specific growth factors may induce caveolin-1 expression in the absence of testosterone sustaining cell survival. A critical molecular link between caveolin-1 and prostate cancer progression was established through the discovery that c-myc overexpression leads to downregulation of caveoline-1 blocks c-myc-induced apoptosis in vitro. He now proposes to characterize the regulation of caveolin-1 gene expression in prostate cancer by gene methylation, testosterone and growth factor-mediated mechanisms. He will also define the cis-acting regulatory elements in the mouse caveolin-1 promoter that mediate transcriptional activation. Based on preliminary data that indicate caveolin-1 can specifically protect against thapsigargin-induced cell death, he will map the biochemical blocks generated by caveolin-1. Finally, he will test the potential cooperative activities of c-myc and caveolin-1 in promoting malignant progression in vitro and in vivo using an LNCaP-mycER system and transgenic prostate and mouse models.
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