Project #3 has been designed to test the hypothesis that the invasive potential of human prostate cancer is determined in part by the relative expression levels of one or several members of the metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) gene families. We have shown that two MMPs, MMP-7 or PUMP-1 and type IV collagenase are overexpressed in primary prostate adenocarcinoma compared to normal prostate. The primary focus in this project will be on the MMP-7 and the TIMP genes. The following specific aims have been designed to test this hypothesis: 1) to characterize the MMP-7 gene in terms of structure, chromosomal localization and transcriptional regulation 2) determine whether the overexpression of MMP-7 in a tumorigenic but weakly invasive and non-metastatic human prostate carcinoma cell line, DU-145, will increase the invasive or metastatic potential when the tumor cells are injected 1.p. or orothotopically into severe combined immuno-deficient (SCID) mice. 3) determine at the levels of messenger RNA and protein the expression of the TIMP 1 and 2 genes in cultured DU-145 and PC-3 human prostate carcinoma cells. 4) determine whether the overexpression of the TIMP 1 gene in a tumorigenic and highly invasive human prostate carcinoma cell line, PC-3, which expressed type I collagenase and invades skeletal muscle when injected 1.p. into SCID mice reduces the invasive behavior of the cell line. the proposed work in this Project will complement the human tissue studies to be carried out in Project #1 and the proposed studies related to the functional role of integrins in prostate tumor cell invasion proposed in Project #2. This Project will utilize both of the Core Projects including the SCID mouse and microscopy cores.
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