The matrix metalloproteinase matrilysin has been implicated in the progression of glandular epithelial tumors. Recently, we have determined that ectopic expression of matrilysin in the mammary glands of transgenic mice results in hyperplastic nodules and acceleration in the development of neu-induced tumors. We have determined that E-cadherin and Fas ligand are substrates for matrilysin, and that cleavage of these substrates can have significant effects on cellular proliferation and apoptosis. Matrilysin gene expression can be modulated by cell:cell interactions and is highly response in changes in cellular architecture. Alterations in Wnt signaling, a-catenin levels, and the Rho family of small G proteins have been shown to modulate matrilysin expression. Taken together, we postulate that matrilysin gene expression is a sensitive indicator of tumorigenic signal transduction pathways that monitor epithelial cell environmental conditions. As a consequence of matrilysin induction, the enzyme further changes the extracellular environment, perpetuating the tumorigenic phenotype and contributing to tumor progression. This hypothesis will be tested with particular emphasis on breast cancer and murine models of mammary carcinogenesis through the following specific aims. 1) Extend the in vivo experiments that test the hypothesis that matrilysin is a tumor promoter for breast cancer using transgenic, chimeric, and matrilysin-null mice, 2) Test the hypothesis that matrilysin effects on tumor progression are mediated by cleavage of E-cadherin and Fas ligand. 3) Determine the signal transduction pathways that modulate matrilysin levels in response to changes in cellular architecture as a means of identifying pathways relevant to early-stage breast cancer. These studies will advance our knowledge of the role of matrilysin in breast cancer, guide the therapeutic application of matrilysin inhibitors to breast cancer patients, and aid in identifying rational new therapeutic targets.
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