The DF3/MUC1 transmembrane protein is aberrantly expressed at high levels on the surface of human breast cancer cells. The functional significance of MUC1 overexpression in breast cancer is unknown. Certain insights have been derived from the finding the cytoplasmic domain of MUC1 associates with members of the catenin family of signaling proteins, beta- catenin, plakoglobin and p120ctn. Beta-catenin interacts with E- cadherin at the cell membrane, with the adenomatous polyposis coli (APC) Protein in the cytosol and with Tcf/LEF-1 as a transcriptional coactivator in the nucleus. Dysregulation of beta-catenin signaling has been associated with the development of diverse human tumors. MUC1 suppresses binding of beta-catenin to E-cadherin and thereby disrupts the adherens junction, an event associated with tumor progression. MUC1 associates with the epidermal growth factor receptor (EGFR), ErbB2 (HER2/neu) and the related ErbB3 and ErbB4 receptor tyrosine kinases. Phosphorylation of the MUC1 cytoplasmic domain by activation of EGFR or the c-Src tyrosine kinase increases the interaction between MUC1 and beta-catenin. By contrast, phosphorylation of MUC1 by glycogen synthase kinase 3beta (GSK3beta), an effector of the Wnt signaling pathway, downregulates the interaction between MUC1 and beta-catenin. Our hypothesis is that, as a consequence of overexpression in breast cancer cells, MUM contributes to i) dysregulation of growth factor signaling through EGFR and the related ErbB2-4 receptors and ii) dysfunction of catenin family members at the cell membrane and in the nucleus. The proposed studies will address this hypothesis and whether MUC1 also functions as a cell surface receptor in breast tumor development.
The Specific Aims are: 1) To define the functional significance of the interaction between MUC1 and the EGF receptor, 2) To determine whether MUC1 interacts with ErbB2 and other members of the ErbB receptor family; 3) To define the effects of MUC1 on ErbB receptor-mediated signaling of catenins at the cell membrane and in the nucleus; and 4) To identify ligands that function in directly activating MUC1 as a cell surface receptor.
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