Using the mouse prostate reconstitution (MPR) model system we demonstrated that loss of p53 function can potentiate prostate cancer metastasis in vivo. Further studies using molecular analysis and/or immunohistochemical staining of human prostate cancer tissues demonstrated that p53 mutations occur at a low frequency in primary tumors but at a significantly higher frequency in metastatic lesions and that prostate cancer cells with specific p53 mutations are expanded clonally in metastases relative to the primary tumor. Overall the results support a specific metastasis suppressor role for p53 in prostate cancer. To investigate this basic concept, we generated a system designed to identify genes under the transcriptional control of p53 using adenoviral-vector-delivered wild type p53 in p53 (-1-) mouse prostate cancer cells generated from the MPR model system and differential display-PCR technology. One of the cDNA sequences that we identified (designated PERP/PIGPC 1) encoded a novel member of the PMP22/Gas3 gene family that is characterized by a potential four transmembrane domain structure. In situ hybridization studies revealed that PERP/PIGPC1 mRNA is at very low abundance in mouse and human normal prostatic epithelial cells but is highly expressed in primary and metastatic mouse and human prostate cancer cells. Paradoxically, PERP/PIGPC1 overexpression can suppress growth of prostate cancer cells in vitro. Another cDNA sequence induced by p53 encoded RTVP- 1. In contrast to PERP/PIGPC 1, in situ hybridization demonstrated that RTVP- 1 mRNA is abundant in normal mouse and human prostate epithelial cells but is significantly reduced in metastases. We have recently demonstrated that overexpression of RTVP- 1 in prostate cancer cells results in activities consistent with it being a specific metastasis suppressor gene including: (1) induction of apoptosis, (2) anti-angiogenic activities, and interestingly, (3) the induction of an antitumor immune response. We hypothesize that the loss of RTVP- 1 activity following p53 mutation or through other mechanisms contributes to prostate cancer metastasis through the abrogation of its apoptotic, anti-angiogenic and immunostimulatory functions. The experiments described in this proposal will test this hypothesis and elucidate fundamental mechanisms of gene regulation of PERP/PIGPC 1 and RTVP- 1 in prostate cancer progression. prostate cancer progression.
Showing the most recent 10 out of 65 publications
