Effects of Surgical vs. Non-Surgical Weight Loss on Mammary Tumor Burden

Abstract

Abstract Background: Obesity is associated with increased incidence of basal-like breast cancer (BLBC), the most aggressive and lethal breast cancer subtype. Epidemiological data is conflicting on whether weight loss offers protection against BLBC in obese women; only interventions that typically result in significant sustained weight loss, such as bariatric surgery, produce a consistent anti-cancer benefit. Purpose: We sought to determine the differential effects of surgical and non-surgical weight loss interventions on inflammation, metabolic hormones and tumor burden in a mouse model of pre- menopausal breast cancer. Methods: Mice were fed a low fat control (Con) or high fat diet-induced obesity (DIO) regimen for 15 weeks to model chronic obesity. Obese mice were then randomized to continue the DIO diet (Obese) or receive a surgical or diet weight loss intervention, resulting in formerly obese (FOb)-Surg or FOb-Diet, respectively. FOb-Surg mice were subject to sleeve gastrectomy (∼70% of the stomach excised), while FOb-Diet mice received a low fat diet. FOb-Surg and FOb-Diet mice normalized body weight and body fat percentage to levels seen in the Con group. After weights stabilized, all mice were orthotopically injected with E0771 mammary tumor cells, which model BLBC. Results: At study endpoint, the average tumor weight in FOb-Surg mice was statistically equivalent to Con mice that maintained a healthy weight throughout study. However, the average tumor weight in FOb-Diet mice was statistically equivalent to Obese mice, both groups significantly greater than Con mice. Additionally, FOb-Surg had statistically lower serum insulin and interleukin-6 compared to FOb-Diet and Obese mice, suggesting that the sleeve gastrectomy more effectively reduced obesity-associated inflammation. Conclusion: Our results suggest that the anti-cancer benefit seen with bariatric surgery may be related to a significant reduction in systemic inflammation and growth factor signaling, which did not occur with non-surgical weight loss despite an equivalent amount of weight and body fat loss in FOb-Diet mice. Identifying the mechanisms underlying the protective effects of bariatric surgery against breast cancer could help identify new targets and strategies for breaking the obesity-cancer link.