The Prostaglandin E₂ Receptor EP2 Is Required for Cyclooxygenase 2–Mediated Mammary Hyperplasia

Abstract

Expression of cyclooxygenase 2 (COX-2) in breast cancer correlates with poor prognosis, and COX-2 enzyme inhibitors reduce breast cancer incidence in humans. We recently showed that COX-2 overexpression in the mammary gland of transgenic mice induced mammary cancer. Because prostaglandin E₂ (PGE₂) is the major eicosanoid and because the EP2 subtype of the PGE₂ receptor is highly expressed in the mammary tumors, we tested if this G protein–coupled receptor is required for tumorigenesis. We crossed the MMTV-COX-2 transgenic mice with Ep2^−/− mice and studied tumor development in bigenic mice. Lack of EP2 receptor strongly suppressed COX-2–induced effects such as precocious development of the mammary gland in virgins and the development of mammary hyperplasia in multiparous female mice. Interestingly, the expression of amphiregulin, a potent mammary epithelial cell growth factor was down regulated in mammary glands of Ep2^−/− mice. Total cyclic AMP (cAMP) levels were reduced in Ep2^−/− mammary glands suggesting that PGE₂ signaling via the EP2 receptor activates the G_s/cAMP/protein kinase A pathway. In mammary tumor cell lines, expression of the EP2 receptor followed by treatment with CAY10399, an EP2-specific agonist, strongly induced amphiregulin mRNA levels in a protein kinase A–dependent manner. These data suggest that PGE₂ signaling via the EP2 receptor in mammary epithelial cells regulate mammary gland hyperplasia by the cAMP-dependent induction of amphiregulin. Inhibition of the EP2 pathway in the mammary gland may be a novel approach in the prevention and/or treatment of mammary cancer.