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.