Abstract 5245: Sulindac decreases basal-like mammary tumor burden and proinflammatory mediators in obese mice
Authors: Khatib Subreen A. , Rossi Emily L. , Bowers Laura W. , Dannenberg Andrew J. , Hursting Stephen D. 
Published: July 2016

Background: A hallmark of the metabolic dysregulation associated with obesity is a pro-inflammatory environment perpetuated by pro-inflammatory mediators including adipokines and growth factor signaling. 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 Sulindac, a nonsteroidal anti-inflammatory drug (NSAID), can reduce chronic obesity-related inflammation and subsequent BLBC growth.

Methods: Mice were administered a control diet (10 kcal% fat) or diet-induced obesity regimen (DIO, 60 kcal% fat). After 15 weeks on diet, DIO mice either continued on DIO diet or were switched to the low fat control diet to induce gradual weight loss, resulting in Formerly Obese (FOb) mice. Half of the mice in all three groups (Control, FOb, DIO, n = 17/group) were randomized to receive Sulindac supplementation at 160 ppm in the diet, which remained constant across diets. Twelve weeks after initiating Sulindac supplementation and weight loss in the FOb groups, all mice were orthopically injected with E0771 cells, a model of basal-like breast cancer. Five mice/group were killed, and their tissue collected and stored at a 4-week intermediate time-point after injection, while 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 both control and FOb mice. Interestingly, body weight, body fat percentage, and ex vivo visceral white adipose weight were unchanged between all supplemented and non-supplemented counterparts (i.e. DIO vs. DIO+Sulindac). At the 4-week intermediate time point, Sulindac supplementation in DIO mice (but not in control or FOb mice) significantly reduced mean tumor weight relative to their non-supplemented counterparts. In the survival arm of the study, Sulindac significantly increased tumor latency in DIO and FOb groups (but not controls) in comparison to their non-supplemented counterparts.

Conclusions: Sulindac supplementation significantly reduced pro-inflammatory mediators insulin and leptin in DIO mice, and increased tumor latency in DIO and FOb mice. Furthermore, Sulindac supplementation did not modulate body weight or fat depots, suggesting that Sulindac indeed offsets some of the pro-tumorigeneic effects of obesity rather than targeting obesity directly. Ongoing analyses of inflammatory surrogates, including circulating cytokines and prostaglandins, mammary gland crown-like structures and cyclooxygenase-2 levels, will help to determine if Sulindac's effects are mediated through its anti-inflammatory activity.

Citation Format: Subreen A. Khatib, Emily L. Rossi, Laura W. Bowers, Andrew J. Dannenberg, Stephen D. Hursting. Sulindac decreases basal-like mammary tumor burden and proinflammatory mediators in obese mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5245.