期刊
BREAST CANCER RESEARCH AND TREATMENT
卷 123, 期 2, 页码 591-596出版社
SPRINGER
DOI: 10.1007/s10549-010-0834-y
关键词
Aromatase; Metformin; Breast cancer; AMP-activated protein kinase (AMPK); Estrogen; CRTC2
类别
资金
- Victorian Breast Cancer Research Consortium Inc.
- NHMRC of Australia [494819, 494802]
- Victorian Government
- Terry Fox Foundation through National Cancer Institute of Canada
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 mu M. Consistent with the hypothesized actions of metformin to increase AMPK activity, treatment with 50 mu M 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据