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Epidemiological evidence supports a correlation between obesity and breast cancer in women. AMP-activated protein kinase (AMPK) is recognized to be a master regulator of energy homeostasis. One of its actions is to phosphorylate and inhibit the actions of cAMP-responsive element binding protein (CREB)-regulated transcription coactivator 2 (CRTC2). In postmenopausal women, the CREB-dependent regulation of aromatase is a crucial determinant of breast tumor formation through local production of estrogens. We report here that the regulation of aromatase expression in the breast by AMPK and CRTC2, in response to the altered adipokine milieu associated with obesity, provides an important link between obesity and breast cancer risk. Cancer Res; 70(1); 4–7