ECM MEDIATORS OF CHEMOPREVENTIVE AGENTS IN THE BREAST

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We hypothesize that the chemopreventive activity of difluoromethlyornithine (DFMO) and retinoids on MNU-induced mammary carcinogenesis in the Sprague- Dawley rat is a result of changes in mammary stroma. Specifically, we propose that these agents induce stroma-dependent tissue remodeling which results in apoptotic death of mammary epithelial cells. Mammary extracellular matrix (ECM) isolated from chemopreventive agent treated rats under conditions known to induce tissue remodeling will be characterized to identify ECM components that have growth suppressive activity on premetastatic mammary epithelial cells. The characterization of biactive ECM will focus on modular glycoproteins fibronectin laminin, and tenasoin and on the enzymes that control their degradation. Reconstitution experiments with purified protein will be performed to determine cause and effect relationship between specific ECM components and induction of tissue remodeling enzymes and epithelial cell death. The results from this work will contribute directly to understanding the role of ECM in regulating apoptotic cell death in mammary epithelial cells and will elucidate whether ECM can be targeted by chemopreventive agents in order to control mammary carcinogenesis.