Abstract 2689: The protumorigenic, proinflammatory effects of obesity are reversed by weight loss via bariatric surgery, but not a low-fat diet

Abstract

Abstract Background: Obesity negatively impacts basal-like breast cancer (BLBC) prognosis, but the reversibility of these pro-cancer effects via weight loss remains unclear. However, there is consistent evidence suggesting that weight loss via bariatric surgery reduces breast cancer risk. This may be related to the reductions in metabolic perturbations and inflammation that follow bariatric surgery, effects that could be mediated by epigenetic reprogramming and/or changes in the gut microbiome. Purpose: We previously demonstrated that mammary tumor growth and inflammation remain elevated in formerly obese mice, in concordance with aberrant methylation of inflammation-related genes. Here we aim to determine the differential effects of surgical versus non-surgical weight loss on inflammation, DNA methylation, the gut microbiome, and tumor burden in a mouse model of BLBC. Methods: Mice were fed a low fat control (n=25) or high fat diet-induced obesity (DIO, n=75) regimen for 15 weeks to model chronic obesity. DIO mice were then randomized to remain on DIO (Obese) or receive either a surgical (sleeve gastrectomy) or dietary (low fat control diet) weight loss intervention, resulting in formerly obese (FOb)-Surg or FOb-Diet mice, respectively. The Control mice were maintained on the low fat diet throughout study. Four weeks after weight stabilization in the FOb mice, all mice were orthotopically injected with E0771 mammary tumor cells, which model BLBC. Stool samples were collected at baseline and prior to tumor cell injection. Results: The average weight and percent body fat of the FOb-Surg and FOb-Diet mice were equivalent to Control and significantly lower than Obese mice at study endpoint. Average tumor weight in FOb-Surg mice was statistically equivalent to Control mice, but tumor weight in FOb-Diet mice was significantly greater than Control mice and statistically equivalent to Obese mice. Furthermore, FOb-Surg mice had significantly lower serum tumor necrosis factor alpha, mammary gland interleukin-6 expression, and tumor-infiltrating adipocyte area in comparison to FOb-Diet. To further define the effects of surgical versus non-surgical weight loss, characterization of the gut microbiota as well as global mammary tissue gene expression and DNA methylation via paired RNA sequencing and reduced representation bisulfide sequencing is in progress. Conclusions: Our results suggest that the strong anti-cancer benefits seen with bariatric surgery may be related to a significant reduction in systemic and local inflammation, which did not occur with non-surgical weight loss. Identification of the mechanisms mediating the protective effects of bariatric surgery against breast cancer could help identify new targets and strategies for breaking the obesity-cancer link. Citation Format: Laura W. Bowers, Emily L. Rossi, Subreen A. Khatib, Steven Doerstling, Alfor Lewis, Randy J. Seeley, Stephen D. Hursting. The protumorigenic, proinflammatory effects of obesity are reversed by weight loss via bariatric surgery, but not a low-fat diet [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 2689. doi:10.1158/1538-7445.AM2017-2689