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Journal of Lipid Research, Vol. 46, 2636-2648, December 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Coupling of COX-1 to mPGES1 for prostaglandin E₂ biosynthesis in the murine mammary gland

Subhashini Chandrasekharan^*, Nicholas A. Foley^*, Leigh Jania^*, Patsy Clark, Laurent P. Audoly and Beverly H. Koller^1,*

^* Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec H9H 3L1, Canada

Published, JLR Papers in Press, October 3, 2005. DOI 10.1194/jlr.M500213-JLR200

¹ To whom correspondence should be addressed. e-mail: treawouns{at}aol.com

The mammary gland, like most tissues, produces measurable amounts of prostaglandin E₂ (PGE₂), a metabolite of arachidonic acid produced by sequential actions of two cyclooxygenases (COX-1 and COX-2) and three terminal PGE synthases: microsomal prostaglandin E₂ synthase-1 (mPGES1), mPGES2, and cytosolic prostaglandin E₂ synthase (cPGES). High PGE₂ levels and COX-2 overexpression are frequently detected in mammary tumors and cell lines. However, less is known about PGE₂ metabolic enzymes in the context of normal mammary development. Additionally, the primary COX partnerships of terminal PGE synthases and their contribution to normal mammary PGE₂ biosynthesis are poorly understood. We demonstrate that expression of COX-1, generally considered constitutive, increases dramatically with lactogenic differentiation of the murine mammary gland. Concordantly, total PGE₂ levels increase throughout mammary development, with highest levels measured in lactating tissue and breast milk. In contrast, COX-2 expression is extremely low, with only a modest increase detected during mammary involution. Expression of the G_s-coupled PGE₂ receptors, EP2 and EP4, is also temporally regulated, with highest levels detected at stages of maximal proliferation. PGE₂ production is dependent on COX-1, as PGE₂ levels are nearly undetectable in COX-1-deficient mammary glands. Interestingly, PGE₂ levels are similarly reduced in lactating glands of mPGES1-deficient mice, indicating that PGE₂ biosynthesis results from the coordinated activity of COX-1 and mPGES1.

We thus provide evidence for the first time of functional coupling between COX-1 and mPGES1 in the murine mammary gland in vivo.

Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; cPGES, cytosolic prostaglandin E₂ synthase; LC-MS, liquid chromatography-mass spectrometry; mPGES, microsomal prostaglandin E₂ synthase; PGDH, NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase; PGE₂, prostaglandin E₂; PGH₂, prostaglandin endoperoxide; PR, progesterone receptor; TXB₂, thromboxane B₂; VEGF, vascular endothelial growth factor

Supplementary key words prostanoid • eicosanoid • metabolism • gene regulation • prostaglandin E₂ receptors • EP2 • EP4 • mouse mammary development • microsomal prostaglandin E₂ synthase-1 • cytosolic prostaglandin E₂ synthase • cyclooxygenase-1

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