Biochemical and molecular mechanisms for the association between obesity, chronic inflammation, and breast cancer

Upper body obesity is a risk factor for postmenopausal breast cancer and is related to an aggressive tumor phenotype and a poor prognosis regardless of menopausal status. After the menopause, the major mechanism for the association with disease risk is elevated estrogen production by adipose tissue, due to a high level of aromatase activity: these hormone-dependent tumors express both estrogen and progesterone receptors. Other important biological factors of risk include leptin and adiponectin, adipokines with opposing endocrine and paracrine activities, and obesity-related hyperinsulinemia. Chronic inflammation of the breast adipose tissue, which occurs in some obese women and is indicated by the accumulation of macrophages around dead adipocytes ("crown-like structures"), rather than adiposity per se, may prove to be the pathological lesion responsible for both local aromatase induction, and enhanced invasiveness and metastatic capacity through biological mechanisms that involve leptin, tumor necrosis factor-α, and insulin. A causal association between obesity in premenopausal women and breast cell epithelial-mesenchymal transition, perhaps with the participation of the Wnt signaling pathway, and aggressive hormone-independent breast cancer is suggested by a number of experimental and clinical studies.