Metformin Inhibits Aromatase Expression in Primary Human Breast Adipose Stromal Cells.
Authors: K. Brown, K. Brown, E. Simpson, E. Simpson
Journal: Cancer Research (2009)

Abstract There is good epidemiological evidence that obesity is linked to an increased risk of cancers such as colon and breast. Given the obesity problem worldwide, it is now believed that tens of millions more women may contract breast cancer in their senior years than was previously thought. After menopause, when the ovaries have ceased to produce estrogens, it is the local expression of aromatase, the enzyme responsible for converting androgens to estrogens, within the breast adipose that is believed to be responsible for the increased proliferation of breast cancer cells.We have recently demonstrated that the LKB1/AMPK pathway is inhibitory of aromatase expression in primary human breast adipose stromal cells by inhibiting the nuclear entry of CRTC2, a CREB co-activator. Factors produced in obesity, such as leptin, and by tumors, such as PGE2, were shown to inhibit LKB1 expression and activity and cause the nuclear translocation of CRTC2, resulting in the increased expression of aromatase. Conversely, a factor produced in lean individuals, adiponectin, and the drug AICAR, known to activate AMPK, inhibited the PGE2-mediated expression of aromatase.There is growing evidence that the action of metformin, an oral anti-diabetic drug which has been used for many years, is mediated primarily by stimulation of AMPK, in association with interaction with its upstream kinase LKB1. In the present study, we aimed to examine the effect of metformin on aromatase expression and on the LKB1/AMPK pathway within the breast. Primary human breast adipose stromal cells obtained from breast reduction surgeries were treated with increasing amounts of 1,1-dimethylbiguanide hydrochloride (metformin) and aromatase transcript expression was quantified using real-time PCR. Interestingly, 24 hour treatment with metformin resulted in the dose-dependent inhibition of aromatase expression at concentrations of 10 and 50 uM. LKB1 activity was measured by examining the phosphorylation of AMPK by Western blotting and consistent with the proposed role of LKB1/AMPK in aromatase expression, metformin caused a significant increase in AMPK phosphorylation.Phase III aromatase inhibitors are proving highly successful as endocrine therapy for breast cancer in post-menopausal women, replacing Tamoxifen as frontline, second line and neoadjuvant therapy. However long-term contraindications such as bone loss, arthralgia, adverse cardiovascular effects and possibly cognitive defects may limit the use of these compounds in the prevention setting. Moreover, aromatase expression may be only one of several pathways whereby obesity influences breast cancer development. This study suggests that using a drug such as metformin which increases insulin sensitivity, causes weight loss and decreases the local biosynthesis of estrogens, may provide a multi-facetted approach at preventing and treating obesity-related postmenopausal estrogen-dependent breast cancer.Work supported by NHMRC project grant 494819 and the Terry Fox Foundation Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3132.