Melatonin suppresses aromatase expression and activity in breast cancer associated fibroblasts

The main biological active substance secreted by the pineal gland, melatonin (MLT), counteracts the effects of estrogens in breast cancer via exerting a number of its own oncostatic properties. Recent studies of postmenopausal women have identified that the major metabolite of MLT is statistically significantly associated with a lower risk of developing breast cancer. While MLT production decreases with age, breast cancer risk, however, increases with age and obesity. We hypothesize that MLT inhibits estrogen production in breast adipose fibroblasts (BAFs), the main local source of estrogen in breast tumors of postmenopausal women, by inhibiting transcription of the CYP19A1 gene that encodes the key enzyme aromatase. Normal BAFs were cultured from women undergoing breast reduction surgery, while breast cancer-associated fibroblasts (CAFs) were isolated from three women with estrogen receptor (ER) positive invasive ductal carcinomas. MTNR1A and MTNR1B receptor expression and CYP19A1 mRNA expression following MLT treatments were determined by qRT-PCR. BAFs express the G-protein coupled MLT receptors MTNR1A and MTNR1B with elevated levels of MTNR1A found in CAFs. Treatment of BAFs and CAFs with MLT resulted in significant suppression of CYP19A1 transcription and aromatase activity at pharmacological, physiological and sub-physiological concentrations. MLT suppression occurred through promoter-specific PI.4-, PI.3- and PII-derived CYP19A1 mRNA. Stimulation of CYP19A1 PII-mRNA and aromatase activity by prostaglandin E(2) (PGE(2)) were significantly attenuated by physiological doses of MLT. Lower levels of MLT in aging women may increase the risk of progressing ER-positive breast cancer through a decreased ability to suppress CYP19A1 expression and subsequent local estrogen production in BAFs/CAFs.