Ligand independent activation of overexpressed growth factor receptors frequently results in unchecked mitogenesis and inhibition of apoptosis during breast cancer progression. The erbB transmembrane tyrosine kinases are commonly overexpressed in breast cancer tissues and have a potent mitogenic and anti-apoptotic effect. The tumor antigen MUC1 is also commonly overexpressed on breast cancer epithelium, associates with and is phosphorylated by erbB receptor kinases and can potentiate erbBdependent Map Kinase activation. Importantly, interactions between MUC1 and the erbB receptors are observed primarily in tumors and lymph node metastases from infiltrating ductal breast adenocarcinoma patients, and not in normal breast epithelium. We hypothesize that a functional interaction between MUC1 and erbB receptor kinases results in tumor growth and metastatic progression, and acts to drive cells into growth factor-independent mitogenesis and resistance to apoptosis. We intend to investigate the functional significance of molecular interactions occurring between MUC1 and the erbB receptors in the WAP-TGFalpha and MMTV-MUC1 transgenic mouse models of breast cancer. We will determine if erbB kinase activation is required for MUC1-induced tumorigenesis, and if MUC1 expression promotes erbB-induced tumorigenesis by crossing these transgenics onto a Muc1 null and erbB-mutant background, respectively. We will determine if MUC1 and erbB receptor complex formations are tumor-specific, what erbB-specific signaling pathways are activated in tumors, and how downstream effects such as growth, inhibition of apoptosis and invasion are affected by MUC1 and erbB receptor functional interactions. The utilization of mouse models allows us to gain a more comprehensive understanding of both the molecular events occurring in the cell, and how those events contribute to the growth of a spontaneous tumor that is fully affected by the microenvironment. We will next dissect the mechanism by which MUC1 expression affects erbB receptor function in breast cancer cell lines. We will determine if MUC1 expression promotes the recruitment of adapter molecules to erbB receptors, what is the functional outcome of this biochemical interaction and how the expression or ablation of MUC1 affects erbB-dependent signaling. We will also determine if MUC1 expression affects erbB receptor endocytosis, by promoting erbB receptor retention at the plasma membrane or in signaling endosomes, thereby potentiating erbB signaling during transformation.
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