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Division of Medicinal Chemistry and Pharmacognosy (E.S.D.-C., R.W.B.), College of Pharmacy; and Division of Hematology and Oncology (C.L.S.), Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210
Address all correspondence and requests for reprints to: Robert W. Brueggemeier, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210. E-mail: Brueggemeier.1{at}osu.edu.
Estradiol is biosynthesized from androgens by the aromatase enzyme complex. Previous studies suggest a strong association between aromatase (CYP19) gene expression and the expression of cyclooxygenase (COX) genes. Our hypothesis is that higher levels of COX-2 expression result in higher levels of prostaglandin E2, which, in turn, increases CYP19 expression through increases in intracellular cAMP levels. This biochemical mechanism may explain the beneficial effects of nonsteroidal antiinflammatory drugs on breast cancer. The effects of nonsteroidal antiinflammatory drugs, COX-1 and COX-2 selective inhibitors on aromatase activity and expression were studied in human breast cancer cells. The data from these experiments revealed dose-dependent decreases in aromatase activity after treatment with all agents. Real-time PCR analysis of aromatase gene expression showed a significant decrease in mRNA levels when compared with control for all agents. These results were consistent with enzyme activity data, suggesting that the effect of COX inhibitors on aromatase begins at the transcriptional level. Exon-specific real-time PCR studies suggest that promoters I.3, I.4, and II are involved in this process. Thus, COX inhibitors decrease aromatase mRNA expression and enzymatic activity in human breast cancer cells in culture, suggesting that these agents may be useful in suppressing local estrogen biosynthesis in the treatment of hormone-dependent breast cancer.
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