Abstract 1456: Prostaglandin E2 receptor EP1 as a metastasis suppressor in breast cancer

Abstract

Abstract The cyclooxygenase-2 enzyme (COX-2) is highly expressed in breast cancer and contributes to the metastatic process. Inhibition of COX-2 can decrease breast tumor growth and metastasis. Prostaglandin E2 (PGE2), the chief COX-2 product in tumors, has been identified as a predominant protumorigenic prostanoid. PGE2 mediates biological effects by binding to each of four EP receptors (EP1-4). EP1 is coupled to calcium mobilization and PKC; whereas, EP2 and EP4 activate PKA/cAMP, PI3K and ERK pathways. EP3 generally inhibits cAMP levels. EP4, expressed on malignant breast cells, promotes metastasis, but a role for EP1 in metastasis has not been investigated. Using a combination of immunohistochemistry, pharmacologic and genetic approaches, we studied EP1 expression in human breast tissue and function in a murine model of breast cancer metastasis. Our published studies indicate that EP1 was detected by immunohistochemistry in the cytoplasm and nucleus of benign ducts and malignant cells in invasive ductal carcinomas. Overall survival for women with tumors that were negative for nuclear EP1 was significantly worse than for women with EP1 expression. Additionally, pharmacologic antagonism and reduction of EP1 expression by shRNA increased metastatic capacity in our murine model of metastatic breast cancer. These data suggested that EP1 may function as a metastasis suppressor. We now report that murine mammary tumor cell lines 410, 410.4 and 66.1 have decreased mRNA levels of EP1 compared to normal murine mammary epithelial cell line EpH4. The EP1 receptor is normally coupled to calcium mobilization. Even though EP1 expression is decreased in mammary tumor cell lines, preliminary studies suggest the existence of functional EP1 receptor as PGE2 is capable of inducing calcium mobilization in 410.4 cells. In addition, treatment of 410 and 66.1 cells with 5-azacytidine is capable of increasing EP1 mRNA levels which may identify a clinically relevant strategy to increase expression of this protective receptor. We have also identified the presence of a variant EP1 (EP1v) transcript in this murine metastatic breast cancer model. EP1v has been identified previously in murine mast cell line MC/9 and in rat uterus; however, this is the first report that EP1v has been identified in malignant cells. Like EP1, mRNA expression of EP1v is also decreased in 410, 410.4 and 66.1 cell lines compared to EpH4 cells. Our published studies show that EP1 acts to suppress metastasis and we are currently exploring the contribution of EP1v to this mechanism. These findings suggest that EP1 has the potential to be a new therapeutic target in reducing breast cancer metastasis and increasing overall cancer survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1456. doi:10.1158/1538-7445.AM2011-1456