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

¹ Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut; ² Division of Nephrology and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee; and ³ Department of Biological Chemistry, University of California, Los Angeles, California

Requests for reprints: Timothy Hla, Center for Vascular Biology, Department of Cell Biology, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT 06030-3501. Phone: 860-679-4128; Fax: 860-679-1269; E-mail: hla{at}nso2.uchc.edu.

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.

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