Abstract IA046: Mechanistic targets and strategies to break the obesity-cancer link

Abstract

Abstract Obesity promotes the incidence and progression of many cancers including breast cancer. Mechanisms underpinning obesity-driven breast cancer that could be harnessed to intercept this deleterious relationship are not completely understood. Here we apply multi-omics analysis of tumor and adipose to delineate candidate mediators underlying the procancer effects of obesity, and anticancer effects of weight loss, in a mouse model of obesity-driven breast cancer. We modeled bariatric surgery and nonsurgical weight loss in obese C57BL/6NCrl mice fed a high-fat diet (60 kcal% fat) using vertical sleeve gastrectomy or a sham surgery paired with (i) dietary weight loss via ad libitum low-fat diet (10 kcal% fat), (ii) 30% chronic calorie restriction, or (iii) intermittent calorie restriction. Once weight loss stabilized, mammary tumors were induced by orthotopic transplantation of E0771 cells, a model of triple negative breast cancer (TNBC). While bariatric surgery and a switch to low-fat diet were each moderately effective at reducing tumor mass, chronic and intermittent calorie restriction regimens were each highly effective in reducing tumor burden. Tumor transcriptomic analysis using gene set enrichment analysis revealed that weight loss interventions reversed obesity-associated immunosuppression. Mediation analysis identified weight loss and fat mass loss as significant mediators of the reduced tumor mass seen in all interventions. Integration of adipose transcriptomics and reduced-representation bisulfite sequencing identified NFKB1, FXR1, and BACH1 as regulators overrepresented in differentially methylated genes, and conserved with predicted regulators of transcriptional remodeling in human adipose tissue following bariatric surgery. These data indicate that weight loss through dietary and surgical means promotes antitumor immunity, in part via remodeling of tumor adjacent adipose tissue. We have identified several candidate mediators of adipose remodeling that may underpin the antitumor effects of bariatric surgery, and these mediators represent potential mechanism-based targets for future interventions. Citation Format: Michael F. Coleman. Mechanistic targets and strategies to break the obesity-cancer link [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr IA046.