Journal
CANCER RESEARCH
Volume 65, Issue 11, Pages 4496-4499Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-05-0129
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Funding
- NCI NIH HHS [CA77839, CA95181] Funding Source: Medline
- NIGMS NIH HHS [GM15431] Funding Source: Medline
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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 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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