The overall goal of this study is to investigate the role of TGF-b in stromal-epithelial interactions during normal mammary gland development and tumor progression. Breast Cancefls the second leading cause of cancer deaths among women. Recently, it has become clear that a better understanding of mammary gland development will provide a basis for continued advances in detecting, preventing and treating breast cancer. TGF-b is a multifunctional factor that controls growth, differentiation and morphogensis in many tissue types including the mammary gland. Previously, we generated transgenic mice that express a dominant-negative mutation of the TGF-b type II receptor in the periductal stroma of the mammary gland. Transgenic mice demonstrated increased lateral branching and increased expression of HGF, a factor previously shown to promote lateral branching. The data suggest that endogenous TGF-bs act to limit the amount of lateral branching and that TGF-b and HGF may together coordinate branching morphogenesis. While the importance of the stroma in regulating normal mammary gland development is clear, its role in neoplastic development has gone largely unexplored. We propose that dominant-negative interference of TGF-b signaling in the stroma will alter tumor development in the mammary gland. The overall hypothesis of this study is that TGF-b signaling in the mammary gland stroma regulates the expression of specific genes that affect branching morphogenesis and tumor development. Determination of the mechanism of stromal TGF-b signaling will be undertaken in the following specific aims: 1) To test the hypothesis that HGF is mechanistically involved in TGF-b-mediated regulation of branching morphogenesis and to determine if TGF-b regulates HGF expression through Smad proteins in mammary fibroblasts; 2) To test the hypothesis that dominant- negative interference of TGF-b signaling in the stroma alters mammary tumor development; and 3) To test the hypothesis that altered signaling by TGF-b in the mammary stroma results in changes in gene expression that will potentially influence normal branching or tumor development. The proposed experiments will improve our understanding of stromal-epithelial interactions in the mammary gland.
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| Crowley, Michael R; Bowtell, David; Serra, Rosa (2005) TGF-beta, c-Cbl, and PDGFR-alpha the in mammary stroma. Dev Biol 279:58-72 |
