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Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase

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Abstract

AMP-activated protein kinase (AMPK) is recognized as a master regulator of energy homeostasis. In concert with the AMPK-kinase LKB1, it has been shown to provide a molecular link between obesity and postmenopausal breast cancer via its actions to inhibit aromatase expression, hence estrogen production, within the breast. The anti-diabetic drug metformin is known to increase the activity of AMPK and was therefore hypothesized to inhibit aromatase expression in primary human breast adipose stromal cells. Results demonstrate that metformin significantly decreases the forskolin/phorbol ester (FSK/PMA)-induced expression of aromatase at concentrations of 10 and 50 μM. Consistent with the hypothesized actions of metformin to increase AMPK activity, treatment with 50 μM metformin results in a significant increase in phosphorylation of AMPK at Thr172. Interestingly, metformin also causes a significant increase in LKB1 protein expression and promoter activity, thereby providing for the first time an additional mechanism by which metformin activates AMPK. Furthermore, metformin inhibits the nuclear translocation of CRTC2, a CREB-coactivator known to increase aromatase expression which is also a direct downstream target of AMPK. Overall, these results suggest that metformin would reduce the local production of estrogens within the breast thereby providing a new key therapeutic tool that could be used in the neoadjuvant and adjuvant settings and conceivably also as a preventative measure in obese women.

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Acknowledgments

This study was supported by the Victorian Breast Cancer Research Consortium Inc., and by Project Grant #494819, Program Grant # 494802 from the NHMRC of Australia and by the Victorian Government’s Operational Infrastructure Support Program. K.A.B. is supported by The Terry Fox Foundation through an award from the National Cancer Institute of Canada.

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Authors and Affiliations

  1. Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, VIC, 3168, Australia

    Kristy A. Brown, Nicole I. Hunger, Maria Docanto & Evan R. Simpson

  2. Department of Physiology, Monash University, Clayton, VIC, 3168, Australia

    Kristy A. Brown

  3. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3168, Australia

    Evan R. Simpson

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  1. Kristy A. Brown
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  2. Nicole I. Hunger
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  3. Maria Docanto
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  4. Evan R. Simpson
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Correspondence to Kristy A. Brown.

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Brown, K.A., Hunger, N.I., Docanto, M. et al. Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase. Breast Cancer Res Treat 123, 591–596 (2010). https://doi.org/10.1007/s10549-010-0834-y

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  • DOI: https://doi.org/10.1007/s10549-010-0834-y

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