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

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 muM. Consistent with the hypothesized actions of metformin to increase AMPK activity, treatment with 50 muM 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.

• Authors: Kristy A Brown, Nicole I Hunger, Maria Docanto, Evan R Simpson
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 123 Issue 2 Pg. 591-6 (Sep 2010) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 20300828 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aromatase Inhibitors
• CRTC2 protein, human
• Transcription Factors
• Colforsin
• Threonine
• Metformin
• Aromatase
• Protein Serine-Threonine Kinases
• STK11 protein, human
• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases
• Tetradecanoylphorbol Acetate

Topics

• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases (metabolism)
• Active Transport, Cell Nucleus
• Adipose Tissue (drug effects, enzymology)
• Animals
• Aromatase (genetics, metabolism)
• Aromatase Inhibitors (pharmacology)
• Binding Sites
• Breast (drug effects, enzymology)
• COS Cells
• Chlorocebus aethiops
• Colforsin (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Activation
• Female
• Humans
• Metformin (pharmacology)
• Phosphorylation
• Promoter Regions, Genetic
• Protein Serine-Threonine Kinases (metabolism)
• Stromal Cells (drug effects, enzymology)
• Tetradecanoylphorbol Acetate (pharmacology)
• Threonine
• Transcription Factors (genetics, metabolism)
• Transfection