Our goal is to dissect the intercellular signaling mechanisms involved in the initial specification of mammary gland tissue, and those that regulate proliferation, branching morphogenesis and cell polarity at successive stages of mammary development. Breast cancer involves dysregulation of cellular processes such as proliferation, changes in cell adhesion and motility, and invasion of epithelial cells into a stroma, that occur normally in mammary development. Delineating the molecular mechanisms underlying mammary morphogenesis will thus help to identify novel therapeutic targets for breast cancer, as well as improving our understanding of developmental syndromes. This proposal focuses on the role in normal mammary development of the WNT/beta-catenin signaling pathway, which is dysregulated in breast cancer and, when hyperactivated, causes mammary tumors in mice. We have shown that WNT/beta-catenin signaling is essential for initiation of mammary placode formation in embryogenesis. WNT/beta-catenin signaling activity is initially activated in broad streaks along the embryonic mammary lines, and gradually becomes upregulated at sites of mammary placode formation and downregulated between the placode sites. Negative regulation of WNT activity is essential to control organ size, prevent formation of ectopic mammary glands, and suppress the potential for tumorigenesis. We discovered that the secreted WNT inhibitor Dickkopf 4 is WNT-regulated in the surface ectoderm and is expressed at the earliest stages of mammary development, suggesting it as a potential negative feedback regulator of WNT activity. We will use gain and loss of function approaches to test the hypothesis that Dkk4 is required for limiting the size and spacing of mammary placodes. We find that WNT/beta-catenin signaling is reactivated later in embryonic mammary development, accompanying the initial branching of the mammary rudiment. We will use genetic approaches to determine whether WNT signaling is necessary for this initial branching morphogenesis. We discovered that WNT/beta- catenin signaling is active in puberty when the gland undergoes extensive ductal outgrowth and branching in response to estrogen. We will test the hypothesis that WNT signaling is required for progenitor cell expansion in puberty that supports the substantial growth occurring at this stage. Finally, as non-canonical WNT ligands that direct beta-catenin independent signaling pathways are expressed in a dynamic fashion in mammary tissue and show altered expression in breast cancer, we hypothesize that non-canonical WNT signaling contributes to mammary development. We will test this hypothesis by examining the effects of null mutations of non-canonical pathway components on mammary development in vivo.
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