Promoter-specific effects of metformin on aromatase transcript expression

Phase III aromatase inhibitors (AIs) are proving successful in the treatment of hormone-dependent postmenopausal breast cancer. Side-effects associated with total body aromatase inhibition have prompted new research into the development of breast-specific AIs. The identification of tissue- and disease-specific usage of aromatase promoters has made the inhibition of aromatase at the transcriptional level an interesting approach. We have previously demonstrated that AMPK-activating drugs, including metformin, were potent inhibitors of aromatase expression in primary human breast adipose stromal cells (hASCs). This study examines the promoter-specific effects of metformin on inhibiting aromatase expression in hASCs. Tumour-associated promoters PII/PI3 were activated using forskolin (FSK)/phorbol ester (PMA), whereas normal adipose associated promoter PI.4 was activated using dexamethasone (DEX)/tumour necrosis factor-a (TNF alpha). Results demonstrate that metformin significantly decreased the FSK/PMA-, but not the DEX/TNF alpha-mediated expression of total aromatase at concentrations of 10, 20, and 50 mu M (P <= 0.05). Using PCR to amplify promoter-specific transcripts of aromatase, it appears that the inhibition of the FSK/PMA-mediated expression of aromatase is due to decreases in PII/PI.3-specific transcripts, whereas no effect of metformin is observed on any promoter-specific transcript, including PI.4, in DEX/TNF alpha-treated hASCs. This report therefore supports the hypothesis that metformin would act as a breast-specific inhibitor of aromatase expression in the context of postmenopausal breast cancer. (c) 2011 Elsevier Inc. All rights reserved.