The global objective of this research is to elucidate the molecular mechanisms underlying tissue remodeling during growth, differentiation and development in mouse mammary gland, and to gain insights into how this process goes awry in pathologic disorders, including cancer. A central issue in achieving this goal is to understand how the stromal microenvironment regulates the invasive behavior of normal epithelia during pubertal development and how mammary luminal and myoepithelial cells interact to form a stable ductal tree. Extracellular matrix (ECM)-degrading matrix metalloproteinases (MMPs) are expressed in the stroma. They play a role in normal tissue remodeling during development and also contribute to the pathogenesis of tumor progression. The present proposal addresses the mechanisms by which these stromal MMPs orchestrate the cross talk between mesenchymal and epithelial compartments. The goal for this proposal is to dissect, in molecular and cell biological detail, how MMPs affect branching morphogenesis through their ability to orchestrate the stromal microenvironment of the breast. The project will use a toolbox of genetically modified mice and mammary cells, organotypic cell culture models and in vivo transplantation systems to interrogate these models and determine the critical substrates of MMPs, what signaling pathways are regulated by MMPs and how intercellular communication is affected by MMPs. The organotypic cultures will be analyzed for growth, morphogenesis, differentiation, and invasive behavior using a combination of live cell imaging, biochemistry and cell biology. In vivo analysis will utilize genetically modified mammary glands and orthotopic transplants of mammary epithelial cells transduced with wild type and mutated MMPs, their inhibitors and substrates. The role of MMPs in fine-tuning intercellular communication during branching morphogenesis will be studied with emphasize on myoepithelial cells. The study will focus on candidate substrates in the Wnt pathway for MMP3/stromelysin, and how their cleavage by MMPs affects signaling in the mammary epithelium. By dissecting how these signaling pathways operate in balancing stem cell activation, proliferation and differentiation and the mechanical environment in the pubertal mammary gland, the applications to breast cancer should continue to unfold. These experiments will give insights into how misregulation of MMPs directly leads to the development of breast cancer. An understanding of how MMPs function in the normal tissue and how disruption of their function promotes neoplasia is necessary to achieve the long-term goal of finding cures for breast cancer.
Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. This study addresses an important aspect of women's health, of how matrix metalloproteinases regulate normal and neoplastic mammary gland function. The approaches used in this project will elucidate how MMPs alter the structural microenvironment, and how this influences the critical responses of growth and invasion in normal and abnormal mammary gland epithelium and stroma. These studies may form the basis of intervention and therapy in breast cancer, potentially in the premalignant lesions.
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