Submitted on May 25, 2005
Revised on September 2, 2005
Accepted on October 3, 2005
Coupling of COX-1 to MPGES-1 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
Genetics Dept., University of North Carolina- Chapel Hill, Chapel Hill, NC 27599-7264
Corresponding Author: shubha{at}med.unc.edu
The mammary gland, like most tissues, produces measurable amounts of PGE2, a metabolite of arachidonic acid produced by sequential actions of one of two cyclooxygenases, (COX-1 and COX-2) and three terminal PGE synthases: mPGES1, mPGES2 and cPGES. High PGE2 levels and COX-2 over-expression 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 Gs 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-/- mice indicating PGE2 biosynthesis results from the coordinate 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.
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