This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Extracellular matrix (ECM)-degrading proteinases of the matrix metalloproteinase (MMP) gene family have been implicated in the pathogenesis of breast neoplastic progression, yet also play a role in normal tissue remodeling. This project tests the hypothesis that MMPs are essential contributors to the interaction between mammary epithelial cells, the adipogenic stroma and the extracellular matdx. We have used genetic analysis in transgenic mice and mammary cultures, to show that MMPs expressed by stromal cells and mammary epithelial cells alter the cellular microenvironment in the mammary gland during development and lead to neoplastic progression. We wish to address the molecular mechanisms by which these MMPs orchestrate the cross-talk between the mesenchymal and epithelial compartments. It is now clear that altering MMP levels and activity affects the phenotype and behavior of mammary epithelial progenitor and ductal cells and stromal cells. We propose to study the structural basis of these alterations in morphogenesis, differentiation, and migratory and invasive behavior in separated and interacting populations of cells in various microenvironmental configurations in culture model and during in vivo branching morphogenesis using cells from wild type and MMP mutant mice.
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