Abstract 2014: Metabolic adaptations of obesity-accelerated breast cancer.

Abstract Obesity, defined by a body mass index (BMI) ≥ 30 kg/m2, increases the incidence, morbidity, and mortality of breast cancer (BC). However, the specific mechanisms linking obesity to BC risk remain poorly understood. Obesity is a complex condition that alters both systemic metabolism and the local tumor microenvironment, creating conditions that can promote tumor growth. Among these changes, the specific contribution of elevated lipid levels to BC growth has not been experimentally tested, despite hyperlipidemia being a common feature of obesity and dysregulated lipid metabolism a hallmark of cancer biology.Using dietary and genetic approaches in immune-competent mice, we demonstrate that elevated circulating lipids are sufficient to accelerate the growth of orthotopic models of triple-negative BC, even in the absence of obesity or changes in blood glucose and insulin levels. Conversely, pharmacological reduction of systemic lipids attenuates BC growth in obese mice, implicating circulating lipids as direct drivers of tumor expansionWeight loss (WL), achieved through lifestyle interventions or bariatric surgery, remains the only recommended strategy for women with obesity who are at risk for, BC patients and BC survivors. However, evidence-based dietary guidelines tailored to this population are lacking. In our model, a ketogenic diet which evoked WL but failed to lower systemic lipids, failed to protect against BC growth, underscoring the importance of directly targeting lipid metabolism in obesity-associated BC.Incretin mimetics (IM) or GLP-1 receptor agonists are revolutionizing the treatment of obesity and its metabolic complications, by inducing substantial WL and improving multiple health outcomes. As their use expands, IMs will increasingly be part of the therapeutic landscape for BC patients and survivors with obesity. Yet emerging epidemiological data suggest that IM-induced WL may not reduce postmenopausal BC incidence or improve disease-free survival. Consistent with these observations, our mouse data show that IM-mediated WL alone does not prevent BC progression unless accompanied by healthy dietary changes. Our data further suggest that both systemic improvements and local changes to the tumor mammary fat pad microenvironment play a key role in controlling BC growth. Together, our findings identify lipids as critical drivers of BC growth and highlight the importance of lowering circulating and local lipid levels, beyond achieving weight loss, to mitigate BC risk in individuals with obesity. Citation Format: Amandine Chaix, Keren I. Hilgendorf, Gregory S. Ducker, Edgar J. Hernandez. Metabolic adaptations of obesity-accelerated breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2014.