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Prostaglandin E₂ Regulates Aromatase Activity and Expression in Human Adipose Stromal Cells via Two Distinct Receptor Subtypes

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, Ohio 43210

Address all correspondence and requests for reprints to: Robert W. Brueggemeier, Ph.D., 250 Parks Hall, 500 West 12th Avenue, The Ohio State University, Columbus, Ohio 43210. E-mail: Brueggemeier.1{at}osu.edu.

The aromatase enzyme complex, located primarily in the stromal cells of breast tumors, catalyzes estrogen biosynthesis and is fundamental to hormone-dependent growth of breast cancer. Although an important pharmacological target, the mechanisms by which aromatase is regulated are poorly understood. Thus, regulation of aromatase activity and expression in human breast stromal cells by prostaglandin E₂ (PGE₂) was investigated. PGE₂ exerts its actions via four transmembrane receptors, EP₁, EP₂, EP₃, and EP₄, which coordinate different signal transduction pathways. Using selective receptor agonists and antagonists, the involvement of the EP₁, EP₂, and EP₃ subtypes was assessed. Enzyme activity levels in cultures of disease-free stromal cells were determined using a tritiated water-release assay. PGE₂ and agonists of EP₁ and EP₂ significantly increased aromatase activity levels, which were decreased by the corresponding antagonists. An agonist of EP₃, an inhibitory pathway, antagonized activity levels induced by PGE₂. These results were generally reflective of changes in aromatase protein expression, determined by Western blotting analysis and the pattern of mRNA expression determined by a competitive RT-PCR method. Collectively, the results demonstrate that regulation of aromatase by PGE₂ is complex and may influence the development and progression of hormone-dependent breast cancer.

This work was supported by National Cancer Institute (NCI) Grant R01-CA73698 (to R.W.B.), NIH Grant T32-GM08512 (to J.A.R.), and NCI Grant P30-CA16058.

Abbreviations: 7-APTA, 7-(4'-Amino) phenylthio-1,4-androstaediene-3,17-dione; PGE₂, prostaglandin E₂; PKA, protein kinase A; PKC, protein kinase C; TPA, tetradecanoyl phorbol acetate.

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