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

The mammary gland, like most tissues, produces measurable amounts of prostaglandin E-2 (PGE(2)), a metabolite of arachidonic acid produced by sequential actions of two cyclooxygenases (COX-1 and COX-2) and three terminal PGE synthases: microsomal prostaglandin E-2 synthase-1 (mPGES1), mPGES2, and cytosolic prostaglandin E-2 synthase (cPGES). High PGE(2) levels and COX-2 overexpression are frequently detected in mammary tumors and cell lines. However, less is known about PGE(2) metabolic enzymes in the context of normal mammary development. Additionally, the primary COX partnerships of terminal PGE synthases and their contribution to normal mammary PGE(2) 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 PGE(2) 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 PGE(2) receptors, EP2 and EP4, is also temporally regulated, with highest levels detected at stages of maximal proliferation. PGE(2) production is dependent on COX-1, as PGE(2) levels are nearly undetectable in COX-1-deficient mammary glands. Interestingly, PGE(2) levels are similarly reduced in lactating glands of mPGES1-deficient mice, indicating that PGE(2) 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.