ERB-B-2 EXPRESSION AND RESISTANCE TO TNF KILLING

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Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of their cancer deaths. Most patients succumb to metastatic disease. A critical component of the metastatic cascade is the development of resistance to host defense mechanisms including tumor cell killing by activated macrophages and natural cytotoxic cells. It is now clear that killing by both these immune effector cells involves tumor necrosis factor (TNF). Indeed, resistance to TNF cytotoxicity has been found to correlate with resistance to killing by macrophages and natural killer cells. Amplified expression of the erb-B-2/HER2 oncogene has been recently found to correlate with resistance to the cytotoxic effects of TNF and tumoricidal macrophages. This suggests a mechanism by which a subset of tumor cells might survive elimination by host immune surveillance, thereby allowing their propagation and eventual spread (metastases). The erbB-2 oncogene (also known as HER2) is a membrane tyrosine kinase that plays an important role in carcinogenesis. It is amplified in approximately 30% of primary breast carcinomas where its expression correlates with a poor prognosis. erbB-2 expression also appears to be important in ovarian cancer where its expression correlated with resistance to killing by TNF and lymphokine-activated killer cells. Preliminary studies suggest that A20, a novel zinc finger protein that confers resistance to TNF killing, is induced by erbB-2 amplification and that this is the mechanism responsible for the resistant phenotype. Given this, the Specific Aims of the grant are as follows: 1. To what extent does A20 contribute to TNF-resistance associated with amplification of the HER2/neu/erbF-2 oncogene in breast cancers? 2. Elucidation of the mechanism by which erbB-2 modulates A20 expression. 3. To determine if there is a relationship between A20 expression and TNF-resistance in vitro among human breast cancer cell lines and in vivo biological behavior in athymic mice. 4. To assess A20 expression in normal and malignant human breast tissue specimens and in normal and malignant breast epithelial cells.