Abstract 2233: Breaking the obesity-cancer link: Nutritional modulation of inflammation and epigenetic reprogramming

Purpose: Obesity is associated with poorer breast cancer-specific survival, but there is limited and conflicting evidence to support recommendations of post-treatment weight loss for outcome improvement. Consequently, we have examined the reversibility of the procancer effects of obesity via weight loss using preclinical studies combined with transcriptomic and epigenetic analyses. Methods: C57BL/6 mice were randomized to a low-fat diet (LFD, 10% kcal from fat) or diet-induced obesity (DIO, 60% kcal from fat) regimen. After 15 weeks, DIO mice were randomized to remain on DIO (Obese) or begin 1 of 4 weight loss diets: LFD (formerly obese, FOb), high-carb 30% calorie-restricted (HCCR), low-carb 30% CR (LCCR), or intermittent calorie restriction (ICR). ICR mice received a 70% CR diet 2 days/week. Control mice received the LFD throughout study. At week 25, mice were orthotopically injected with E0771 mouse mammary tumor cells, a model of basal-like breast cancer. All mice were euthanized when a tumor in 1 mouse reached 1.5 cm in diameter. Paired RNA sequencing and reduced representation bisulfite sequencing (RRBS) were performed on normal mammary tissue. Results: At study endpoint, Obese mice had a higher average body weight and body fat percent versus all other groups (P Conclusions: This study demonstrates that weight normalization does not reverse the effects of chronic obesity in a preclinical model of basal-like breast cancer, except when more severe weight loss is achieved via calorie restriction. Multiomic profiling of normal mammary tissue indicated a sustained dysregulation in the transcription and methylation of pro-growth and pro-inflammatory genes, relative to CR mice. Greater understanding of the mechanisms mediating obesity-induced epigenetic reprogramming will enable the development of specific treatment strategies to improve obese breast cancer patient outcomes. Citation Format: Laura W. Bowers, Shannon B. McDonell, Emily Rossi, Stephanie Montgomery, Joel Parker, Stephen D. Hursting. Breaking the obesity-cancer link: Nutritional modulation of inflammation and epigenetic reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2233.