The prostaglandin e 2 receptor EP 2 is required for cyclooxygenase 2-mediated mammary hyperplasia

Sung Hee Chang, Youxi Ai, Richard M. Breyer, Timothy F. Lane, Timothy Hla*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

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 E 2 (PGE 2) is the major eicosanoid and because the EP2 subtype of the PGE 2 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 PGE 2 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 PGE 2 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.

Original languageEnglish (US)
Pages (from-to)4496-4499
Number of pages4
JournalCancer Research
Volume65
Issue number11
DOIs
StatePublished - Jun 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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