Abstract SY01-03: The obesity-inflammation connection: Implications for breast carcinogenesis.

Abstract

Abstract 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 malignancies. 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 dead adipocytes forming crown-like structures (CLS). The synthesis of estrogen 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 (TNF-α, IL-1β, PGE2) 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 mastectomy. 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, these 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 preclinical experiments provide proof-of-principle evidence that obesity-related mammary gland inflammation can be rapidly reversed with caloric restriction. Citation Format: Andrew J. Dannenberg. The obesity-inflammation connection: Implications for breast carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY01-03. doi:10.1158/1538-7445.AM2013-SY01-03