title: Promoter-specific effects of metformin on aromatase transcript expression.
abstract: 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/PI.3 were activated using forskolin (FSK)/phorbol ester (PMA), whereas normal adipose associated promoter PI.4 was activated using dexamethasone (DEX)/tumour necrosis factor-α (TNFα). Results demonstrate that metformin significantly decreased the FSK/PMA-, but not the DEX/TNFα-mediated expression of total aromatase at concentrations of 10, 20, and 50 μM (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/TNFα-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.
authors.affiliation: Prince Henry's Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Nirukshi U
authors.initials: NU
authors.lastname: Samarajeewa
authors.forename: Seungmin
authors.initials: S
authors.lastname: Ham
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Yang
authors.forename: Evan R
authors.initials: ER
authors.lastname: Simpson
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Brown
mesh_terms: D000273:Adipose Tissue / Q000201:enzymology; D001141:Aromatase / Q000235:genetics*; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001940:Breast / Q000201:enzymology*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D017698:Postmenopause; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D017154:Stromal Cells / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D047072:Aromatase Inhibitors; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D003907:Dexamethasone; D008687:Metformin; D001141:Aromatase