Abstract P4-04-16: Obesity-associated systemic interleukin-6 promotes pre-adipocyte aromatase expression via increased breast cancer cell prostaglandin E2 production

Abstract

Abstract Introduction: Obesity is associated with a worse breast cancer prognosis, particularly in estrogen receptor alpha (ERα) positive, postmenopausal patients. Resistance to aromatase inhibitor treatment may be one mechanism mediating this effect, as obese patients have a lower response rate to this class of drugs and higher breast tissue aromatase expression. We hypothesized that obesity-associated circulating factors promote breast cancer cell cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production, resulting in an elevation in pre-adipocyte aromatase expression that enhances breast cancer cell estrogen receptor activity and proliferation. Methods: We utilized an in vitro model of the obese patient’s tumor microenvironment in which cultured MCF-7 breast cancer cells and pre-adipocytes were exposed to pooled serum from obese (OB; BMI≥30.0 kg/m2) or normal weight (N; BMI 18.5-24.9 kg/m2) postmenopausal women. Results: Exposure to OB versus N patient sera significantly increased MCF-7 cell COX-2 expression and PGE2 production. This was coupled with 89% greater pre-adipocyte aromatase expression following culture in conditioned media (CM) from MCF-7 cells exposed to OB versus N patient sera, a difference nullified by treatment of the MCF-7 cells with the COX-2 inhibitor celecoxib during CM generation. Previous analysis of the sera revealed significantly higher interleukin 6 (IL-6) concentrations in the OB versus N patient samples. Depletion of IL-6 from the sera resulted in neutralization of the difference between OB and N CM-stimulated aromatase expression. N CM generated with the addition of IL-6 treatment at the time of N patient sera exposure also induced pre-adipocyte aromatase expression that was statistically equivalent to the OB CM condition. Finally, CM from pre-adipocyte/MCF-7 cell co-cultures exposed to OB patient sera stimulated greater MCF-7 and T47D breast cancer cell ERα activity and proliferation in comparison to N. Conclusions: This study indicates that obesity-associated systemic IL-6 indirectly enhances pre-adipocyte aromatase expression via increased breast cancer cell PGE2 production, thereby promoting greater cancer cell ERα activity and proliferation. Investigation regarding the efficacy of a COX-2 inhibitor/aromatase inhibitor combination therapy in the obese postmenopausal patient population is warranted. Citation Format: Laura W Bowers, Andrew J Brenner, Stephen D Hursting, Rajeshwar R Tekmal, Linda A deGraffenried. Obesity-associated systemic interleukin-6 promotes pre-adipocyte aromatase expression via increased breast cancer cell prostaglandin E2 production [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-04-16.