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 It is well established that there are racial differences in breast cancer incidence as well as overall survival. Death rates due to breast cancer in African-American (AA) women remain 37% higher than in Whites (W) despite lower overall incidence rates. Even when differences in access to health care and other factors are considered, there is still evidence that breast cancer is inherently more aggressive in AA women. It is critical to understand the different biology of breast cancer in AA women in order to reduce disparities in clinical outcome. AA women are more likely to have breast tumors that are negative for estrogen receptor, progesterone receptor and for Her-2/neu receptor and these triple-negative tumors have a relatively poor prognosis due to the development of distant metastases. We have employed a murine model of triple-negative breast cancer to identify mechanisms that contribute to high metastatic potential. The cyclooxygenase-2 (COX-2) enzyme is frequently overexpressed in solid cancers and is associated with a poor prognosis in breast, as well as other malignancies. In tumors, the major COX-2 product is prostaglandin E2 (PGE2). Cellular effects of secreted PGE2 are mediated by four G-protein-coupled receptors, designated EP1-EP4, that are coupled to distinct intracellular signaling pathways. We have shown that blocking COX-2 activity or antagonizing the EP4 receptor reduces breast cancer metastasis. In contrast, the EP1 receptor appears to be protective for metastatic disease since antagonism of this receptor results in more tumor dissemination. These and other studies suggest that balanced expression and signaling through all four EP receptors determines the cellular response to PGE2. Using a microarray approach to compare expression of many genes in breast tumors from AA and W women, we observed that expression of the protective EP1 receptor was significantly lower in tumors from AA women. AA tumors express 50-66% less EP1 mRNA than W breast tumors. EP2, EP3 and EP4 levels were comparable in the two populations. We are exploring the hypothesis that reduced EP1 receptor expression in AA breast cancers contributes to the aggressive behavior of these tumors. Further, that restoring the balance of EP1 and EP4-mediated signaling will reduce metastatic capacity and therefore reduce breast cancer disparities.

First AACR International Conference on the Science of Cancer Health Disparities-- Nov 27-30, 2007; Atlanta, GA