Relationship between aromatase and cyclooxygenases in breast cancer: potential for new therapeutic approaches

Estrogens are biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase. Aromatase is found in several tissues in the body and aromatase (CYP19) gene expression is regulated in a tissue-specific manner via use of alternative promoters. Aromatase transcript expression and enzyme activity in breast tumor tissue is greater than that in the normal breast tissue, and prostaglandins can increase CYP19 expression and aromatase activity in breast cancer cells. Cyclooxygenase (COX) is a key enzyme in the production of prostaglandins. Higher levels of COX-2 isoform were observed in breast cancer tissue when compared to normal breast tissue, and a strong association between CYP19 gene expression and the expression of COX genes are found. Epidemiological studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) may be beneficial in reducing the incidence of breast cancer, although the exact mechanisms remain unclear. Both NSAIDs and COX-selective inhibitors suppress aromatase mRNA expression and enzyme activity in breast cancer cells. Real time PCR results demonstrate that this suppression occurs through regulation of CYP19 expression involving promoters I.4 and II, the promoters involved in the development of breast cancer. High levels of COX-2 expression result in higher levels of prostaglandin E2 (PGE2), which in turn increases CYP19 expression through increases in intracellular cyclic AMP levels and activation of promoter II. Thus, PGE2 produced by COX enzymes may act locally in paracrine and autocrine fashion to increase the biosynthesis of estrogen by aromatase in hormone-dependent breast cancer development.