Obesity is a risk factor for the development of several malignancies including hormone receptor–positive breast cancer in postmenopausal women and has been associated with an increased risk of recurrence and reduced survival. Chronic inflammation increases the risk of multiple tumor types. A link between obesity, breast inflammation and hormone receptor-positive breast cancer was previously unknown. Obesity causes subclinical inflammation in visceral and subcutaneous white adipose tissue, characterized by macrophages surrounding necrotic adipocytes forming crown-like structures (CLS). Estrogen synthesis is catalyzed by aromatase, which is encoded by CYP19. Recently, we found increased numbers of CLS, activation of the NF-κB transcription factor, increased levels of pro-inflammatory mediators and elevated aromatase levels and activity in the mammary glands of obese mice. These preclinical findings raised the possibility that the obesity→inflammation→aromatase axis is important for breast carcinogenesis. Importantly, these findings have now been translated to women. Breast tissue was obtained from women who underwent surgery. CLS of the breast (CLS-B) were found in nearly 50% of patient samples. The severity of breast inflammation, defined as the CLS-B index, correlated with both body mass index and adipocyte size. Consistent with our preclinical findings, increased NF-κB binding activity, increased levels of pro-inflammatory mediators and elevated aromatase expression and activity were found in the inflamed breast tissue of overweight and obese women. Collectively, our results suggest that the obesity→inflammation →aromatase axis is present in the breast tissue of most overweight and obese women and is likely to contribute to the increased risk of hormone receptor-positive breast cancer. The presence of CLS-B may be a biomarker of increased breast cancer risk or poor prognosis. The discovery of the connection between obesity, breast inflammation and changes in the expression of genes linked to breast cancer provides a mechanistic rationale for the development of behavioral, dietary and pharmacological strategies to reduce the risk of breast cancer. Recently conducted caloric restriction experiments provide proof-of-principle evidence that obesity-related mammary gland inflammation can be reversed.
Citation Format: Andrew J. Dannenberg. The obesity-inflammation connection: Implications for breast carcinogenesis. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr PL02-04.