Abstract SY12-03: Obesity, inflammation and breast cancer

Abstract

Abstract Obesity is a risk factor for the development of hormone receptor-positive breast cancer in postmenopausal women. In addition to its impact on breast cancer risk, obesity has been recognized as a poor prognostic factor among breast cancer survivors. Obesity causes subclinical inflammation in visceral and subcutaneous white adipose tissue, characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures (CLS). Estrogen synthesis is catalyzed by aromatase, which is encoded by CYP19. Several pro-inflammatory mediators including PGE2 and TNF-alpha are known inducers of aromatase. Utilizing a combination of preclinical models and human breast tissue samples, we demonstrated that obesity was associated with increased numbers of CLS in the breast (CLS-B), activation of the NF-κB transcription factor, increased levels of pro-inflammatory mediators and elevated aromatase expression. These findings raise the possibility that the obesity-inflammation-aromatase axis is important for understanding the link between obesity and hormone receptor-positive breast cancer in postmenopausal women. To further explore the potential clinical significance of breast adipose inflammation, a retrospective study was carried out to investigate the relationship between CLS-B and breast cancer recurrence. The presence of CLS-B at the time of index mastectomy was associated with shortened recurrence free survival in women who develop recurrent breast cancer. Whether white adipose inflammation promotes the progression of breast cancer via local effects, systemic mechanisms, e.g., hyperinsulinemia or both is uncertain. Given the apparent significance of white adipose inflammation (CLS-B) in the pathogenesis of disease, a blood-based biomarker discovery effort has been initiated. Elevated levels of CRP, IL-6 and insulin as well as altered levels of numerous metabolites correlate with the presence of breast white adipose inflammation. Finally, the connection between obesity, adipose inflammation and cancer provides a strong rationale for attempting to develop effective anti-inflammatory interventions. This will be illustrated with findings from a recent preclinical study that utilized caloric restriction to reverse adipose inflammation and related molecular changes in the mammary glands of obese mice. Citation Format: Andrew J. Dannenberg. Obesity, inflammation and breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY12-03. doi:10.1158/1538-7445.AM2015-SY12-03