Abstract 2694: Target obesity-associated inflammation to decrease murine basal-like mammary tumor burden
Authors: Rossi Emily L. , Khatib Subreen A. , Bowers Laura W. , Doerstling Steven S. , Dannenberg Andrew J. , Hursting Stephen D. 
Published: July 2017

Background: Adipose tissue dysregulation, a hallmark of obesity, contributes to a chronic state of low-grade inflammation that promotes cancer growth through multiple signaling pathways. We previously showed that inflammation and basal-like breast cancer (BLBC) growth are increased in chronically obese mice and persist following weight normalization.

Purpose: We tested the hypothesis that targeting inflammation in obese mice by treating them with the nonsteroidal anti-inflammatory drug (NSAID) Sulindac would offset the procancer effects of obesity in a mouse model of BLBC.

Methods: Mice were administered a control diet (10 kcal % fat; n=34) or diet-induced obesity regimen (DIO, 60 kcal % fat; n=34). After 15 weeks on control or DIO diets, mice were randomized to either receive Sulindac supplementation at 160 ppm in the diet (n=17/diet) or no supplementation (n=17/diet). Twelve weeks later, all mice were orthopically injected with E0771 cells, a model of basal-like breast cancer. Five mice/group were killed at a 4-week interim time-point after injection, and their tissue collected and stored. The remaining 12 mice/group continued in a survival study; these mice were killed when tumor size reached 1.2 cm in diameter in any direction.

Results: Sulindac supplementation in DIO mice significantly reduced serum insulin and leptin to levels statistically equivalent to control mice, but had no effect on body weight, body fat percentage, or ex vivo visceral white adipose weight. Sulindac supplementation in DIO mice (but not control) significantly reduced mean tumor volume in the interim tumor study and significantly increased tumor latency in the survival study. Analysis of H&E stained tumor demonstrated that DIO mice had significantly increased adipocytes infiltrating into the tumor (relative to control), but Sulindac supplementation in DIO mice decreased adipocyte infiltration to levels observed in control.

Conclusions: Sulindac supplementation significantly reduced insulin and leptin in DIO mice, and increased tumor latency in DIO mice, but had no effects on body weight or fat depots, suggesting that Sulindac offsets some of the pro-tumorigeneic effects of obesity rather than targeting obesity directly. Preliminary analyses of inflammatory surrogates, including circulating cytokines and prostaglandins, mammary gland crown-like structures and cyclooxygenase-2 levels, suggests Sulindac’s effects in obese mice are mediated through its eicosanoid-depressing effects.

Citation Format: Emily L. Rossi, Subreen A. Khatib, Laura W. Bowers, Steven S. Doerstling, Andrew J. Dannenberg, Stephen D. Hursting. Target obesity-associated inflammation to decrease murine basal-like mammary tumor burden [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2694. doi:10.1158/1538-7445.AM2017-2694