Abstract 5764: Opposing roles of the COX-2 pathway receptors EP1 and EP4 in metastasis and contribution to disparities

Abstract

Abstract Cyclooxygenase-2 is highly expressed in breast and other malignancies and contributes to a poor prognosis. Our goal is to identify novel approaches to target the COX-2 pathway in order to reduce metastatic potential and improve survival. The primary COX-2 product, prostaglandin E2, exerts cellular effects by binding to four distinct G-protein-coupled receptors designated EP1, EP2, EP3 and EP4. Using pharmacologic and genetic approaches and a preclinical model of metastatic, triple-negative (ER, PR, Her-2 negative) breast cancer, we have examined the role of EP4 and EP1 in malignant behavior. Inhibition of EP4 receptor signaling with selective EP4 antagonists limits breast cancer metastasis to the same degree as achieved with a COX-2 inhibitor. Likewise, gene silencing of EP4 with specific shRNA also limits metastatic capacity by a mechanism involving Natural Killer cells. Conversely, blocking EP1 with either pharmacologic antagonists or genetic ablation promotes tumor metastasis. The expansion of mammary-gland implanted tumors was not affected by changes in EP1 expression levels, indicating that EP1 functions selectively to suppress metastasis. In primary breast tumors or cell lines, EP1 protein is detected both on the plasma membrane and in the nucleus. Immunohistochemical examination of a tissue array containing primary breast tumors reveals that the absence of nuclear EP1 in malignant cells is associated with significantly worse long term survival. Levels of cytoplasmic EP1 were not correlated with differences in outcome. Interestingly, breast tumors from African-American women express significantly less EP1 mRNA than tumors from Caucasian women, suggesting that low EP1 could contribute to worse outcome in AA women. These data support the hypothesis that EP1 acts as a metastasis suppressor but EP4 promotes metastasis and that shifting the balance towards activation of EP1 could be a novel approach to reduce breast cancer metastasis and reduce disparities in outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5764.