title: Molecular pathways: adipose inflammation as a mediator of obesity-associated cancer.
abstract: The increasing rate of obesity worldwide is predicted to be associated with a surge in diseases. Notably, obesity has been linked to approximately 20% of cancer cases in the United States; obesity is associated with both increased risk and worse outcomes after diagnosis. Altered levels of circulating factors are strongly implicated, including insulin, insulin-like growth factor 1, leptin, adiponectin, and interleukin-6 (IL-6). In addition, increasing attention has focused on the consequences of local adipose inflammation. Inflammatory foci characterized by crown-like structures consisting of dead adipocytes encircled by macrophages occur in white adipose depots, including the breast tissue, of most overweight and obese women. Saturated fatty acids, released as a consequence of obesity-associated lipolysis, induce macrophage activation via Toll-like receptor 4, thereby stimulating NF-κB signaling. This, in turn, activates transcription of proinflammatory genes including COX-2, IL-6, IL-1β, and TNFα. Elevated levels of proinflammatory mediators cause both local and systemic effects. Of particular relevance with regard to breast cancer is increased transcription of the CYP19 gene encoding aromatase, the rate-limiting enzyme for estrogen synthesis. Notably, this obesity-inflammation-aromatase axis provides a plausible explanation for increased rates of postmenopausal, hormone receptor-positive breast cancer associated with obesity and hence may offer targets for interventions to attenuate risk or improve prognosis. Potential approaches include weight reduction, exercise, and suppression of obesity-driven signaling pathways using pharmaceutical or dietary agents. A key future goal is to identify biomarkers that accurately report adipose inflammation, both for identification of at-risk individuals and to assess the efficacy of interventions. Clin Cancer Res; 19(22); 6074-83. ©2013 AACR.
authors: Authors' Affiliations: Departments of Cell & Developmental Biology and Medicine, Weill Cornell Medical College; and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Louise R
authors: LR
authors: Howe
authors: Kotha
authors: K
authors: Subbaramaiah
authors: Clifford A
authors: CA
authors: Hudis
authors: Andrew J
authors: AJ
authors: Dannenberg
mesh_terms: D017667:Adipocytes / Q000276:immunology / Q000473:pathology; D000273:Adipose Tissue / Q000276:immunology*; D001141:Aromatase / Q000096:biosynthesis / Q000235:genetics; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D009765:Obesity / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D001141:Aromatase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
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