Our objective is to establish the molecular basis for the contribution of the MUC1 mucin to tumorigenesis and metastasis. MUC1 is a cell associated mucin glycoprotein that is highly overexpressed in greater than 90 percent of carcinomas and metastatic lesions. We showed that spontaneous mammary gland tumors in mice lacking Muc1 had highly significant decreases in tumor growth rate and metastasis. Our hypothesis is that MUC1 is a multi-functional protein with structural features that contribute to its ability to modulate tumor progression and metastasis. One structural feature is the rodlike, densely glycosylated extracellular domain that modulates the adhesiveness of tumor cells and their vulnerability to immune effector cells. The second structural feature is the tyrosine phosphorylated cytoplasmic tail domain that interacts with proteins involved in signal transduction and cytoskeletal reorganization. To test our hypothesis, in aim 1 we will overexpress the human MUC1 protein in mammary glands of mice, directly mimicking the phenotype of MUC1 overexpression in human breast cancer. Development in the normal glands will be studied. These mice will be crossed with MMTV-MTag and MMTV-c-neu mice that develop spontaneous breast cancer and the bitransgenics will be examined for the effects of MUC1 overexpression. We will monitor tumor progression and metastasis. 2) To examine the functional significance of the MUC1 domains, we will overexpress MUC1 in transgenic mice with various domains deleted (tandem repeats, extracellular, and cytoplasmic domains) in normal glands and tumors to test the functions of these regions in tumorigenesis and development. 3) We will identify proteins interacting with MUC1 using the yeast two-hybrid technique and coimmunoprecipitation experiments and characterize the molecular details and consequences of MUC1 interactions with cytoplasmic proteins involved in signal transduction and cytoskeletal organization. The planned experiments will add to our understanding of how MUC1 modulates tumor progression and metastasis by virtue of its rodlike extracellular domains as well as through interactions of the cytoplasmic domain with proteins that are involved in signal transduction.
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