MUC1 is a tumor antigen that is overexpressed on most carcinomas, including greater than 90% of breast carcinomas. This cell associated mucin is highly O-glycosylated and expressed at low levels on normal secretory epithelial tissues. MUC1 expression is greatly increased and the cellular localization is altered in tumors and metastases, where it is found surrounding the entire cell. Although MUC1 does not possess kinase activity, the cytoplasmic tail interacts with multiple signaling and adhesion-regulating proteins. Among these proteins are EGFR, erbB2, 3, and 4, Protein Kinase C delta, c-src, GSK3beta, p120 ctn, beta-catenin, and Grb2. We hypothesize that MUC1 serves as an adaptor protein that brings together kinases, phosphatases, and other adaptor proteins to assemble a complex that leads to tumor formation, possibly by inducing mitogenesis, and/or changes in the adhesive state of the cell. Overexpression of MUC1 in the mouse mammary gland, to mimic what is seen in humans, resulted in stochastic tumor formation in 63% of mice. Ninety percent of tumors metastasized to the lung. No tumors were observed in wildtype mice or mice expressing MUC1 lacking the cytoplasmic tail, suggesting that the cytoplasmic tail is critical to the function. To further characterize the oncogenic function of MUC1 in the mammary gland and other epithelial tissues, we propose: 1) to determine the critical portions of the MUC1 protein involved in tumorigenesis and define down-stream signaling pathways, 2) to determine the role of specific tyrosines in the MUC1 cytoplasmic tail, 3) to characterize additional interactions of the cytoplasmic tail with signaling and tumor suppressor proteins, and 4) to determine if MUC1 is oncogenic in tissues other than the mammary gland. These studies will significantly increase our understanding of the importance of MUC1 function in epithelial tumors during transformation, growth, invasion and metastasis.
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