Interrelationships between cyclooxygenases and aromatase: unraveling the relevance of cyclooxygenase inhibitors in breast cancer

Abstract

Breast cancer is the most common cancer among women, and ranks second among cancer deaths in women. Approximately 60% of all breast cancer patients have hormone-dependent breast cancer, which contains estrogen receptors and requires estrogen for tumor growth. Estradiol is 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 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. Studies have shown higher levels of COX-2 isoform in breast cancer tissue when compared to normal breast tissue, and this is accompanied by high concentrations of prostaglandin E(2) (PGE(2)). Previous studies suggest a strong association between CYP19 gene expression and the expression of COX genes. While studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) have beneficial effects on breast cancer, the mechanism by which this occurs is still unclear. Studies have shown that COX inhibitors decrease aromatase activity in breast cancer cells and this effect starts at the transcriptional level. Real time PCR data shows that this molecular mechanism involves 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 E(2) (PGE(2)), which in turn increases CYP19 expression through increases in intracellular cyclic AMP levels and activation of promoter II. Thus, PGE(2) produced via COX may act locally in paracrine and autocrine fashion to increase the biosynthesis of estrogen by aromatase in hormone-dependent breast cancer development.