The goals of these studies are to determine the role of caveolin-1 in mammary tumorigenesis. The caveolin-1 protein is the essential component of caveolae organelles that regulates signal transduction pathways. Evidence suggesting caveolin-1 is a breast tumor suppressor includes: i) Caveolin-1 inhibits cellular proliferation and anti-sense caveolin-1 promotes contact independent growth of cultured 3T3 cells. ii) Caveolin-1 inhibits cyclin D1 breast cellular proliferation Cyclin D1 anti-sense can inhibit contact-independent growth of mammary tumor cell lines derived from the MMTV-ErbB2 transgenics in vivo). iii). Caveolin-1 levels are reduced in human and murine mammary tumors, including MMTV-ErbB2 derived tumors, and in the majority of breast cancer cell lines. iv). Loss of heterozygosity (LOH) analysis shows CAV1 is within the 7q31.1 region implicated to encode a breast tumor suppressor gene. We hypothesize that caveolin-1 inhibits mammary tumor growth repression of cyclin D1 and induction of the cyclin dependent kinase inhibitor p27. Reduced p27 levels and increased cyclin D1 correlates with poor prognosis in human breast cancer. p27 functions as a haplo- insufficient tumor suppressor of ErbB2-induced mammary tumorigenesis in vivo, transgenic mice, over-expressing caveolin-1 (beta-actin-CMV- enhancer-caveolin), or lacking the caveolin-1 gene (Cav-1/-) were generated. Both types of mice survive and breast feed. Mouse embryo fibroblasts (MEFs) of CAV-1 over-expressing transgenics show reduced cellular proliferation, and delayed S-phase entry and increased apoptosis. In contrast, MEFs derived from Cav-1-/- mice show enhanced cellular proliferation and S-phase entry and reduced cellular apoptosis. The proposed studies will 1). Determine the effect of caveolin-1 over- expression on Neu-induced mammary tumors. 2). Determine the effect of transgenic caveolin-1 on mammary tumor growth in vivo using MMTV- ErbB2 transgenic mice. 3). Determine if genetic ablation of the caveolin- 1 gene predisposes towards mammary tumorigenesis and metastasis in vivo.
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