The long-term objective of this proposal is to understand the role of caveolin-1 in mammary epithelial-stromal interactions, during mammary tumorigenesis (a.k.a., the tumor microenvironment). Here, we will investigate the development of epithelial cell hyperplasia in the mammary glands of Cav-1 null mice. More specifically, we will mechanistically dissect the individual contributions of epithelial or non-epithelial cells to this hyperplastic Cav-1 null phenotype. Using both in vitro and in vivo mammary reconstitution experiments, we will explore whether the specific loss of Cav-1 within mammary epithelial cells or non-epithelial cells (i.e. stromal cells, including fibroblasts and adipocytes) both contribute to a dysregulation of epithelial proliferation and tumorigenesis. The two Specific Aims (SAs) of the project are: SA1) To examine the role of Cav-1 in epithelial-stromal interactions during mammary tumorigenesis. For this purpose, we will explore whether the specific loss of Cav-1 within mammary epithelial cells or non-epithelial cells (i.e. stromal cells, including fibroblasts and adipocytes) both contribute to a dysregulation of epithelial cellular proliferation, hyperplasia, and tumorigenesis, using mammary reconstitution experiments. Additional studies will be carried out with human breast cancer samples to identify CAV-1 mutations in mammary stromal cells. SA2) To determine the effects of Cav-1 expression on Cyclin D1-induced mammary tumorigenesis. In this aim, we will evaluate how Cav-1 expression modulates Cyclin D1-induced mammary tumorigenesis, by crossing Cav-1 (-/-) null and Cav-1 transgenic (Tg) mice, with MMTV-Cyclin D1 transgenic mice. Complementary experiments will be carried out employing the therapeutic administration of a cell permeable caveolin-1-based mimetic peptide. In this context, epithelial-stromal contributions will also be evaluated. These studies will contribute fundamental knowledge toward understanding the role of Cav-1 in regulating epithelial-stromal interactions, during mammary cell transformation and tumorigenesis.
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