Abstract 2576: Calorie restriction reverses the tumorigenic effects of obesity to a greater extent than bariatric surgery in a murine model of breast cancer
Authors: Camp Kristina K. , Rossi Emily , McFarlane Tori L. , Doerstling Steven , Khatib Subreen , Glenny Elaine , Coleman Michael , Bowers Laura , Rezeli Erika , Seeley Randy J. , Lewis Alfor G. , Parker Joel , Fodor Anthony , Fouladi Farnaz , Hursting Stephen 
Published: July 2021

Abstract
Obesity is an established risk and prognostic factor for multiple breast cancer (BC) subtypes. Epidemiologic studies suggest that weight loss via bariatric surgery results in metabolic reprogramming that reverses systemic aberrations as well as the protumorigenic effects of obesity; however, data on the effects of nonsurgical weight loss interventions in obese women remain inconclusive. We previously established that diet-induced obesity (DIO) increases tumor progression in murine models of basal-like BC. The purpose of this study was to determine if surgical and dietary weight loss interventions could effectively reduce obesity-associated tumor progression. Our first experiment directly compared mammary tumor growth following weight loss in DIO mice. Female C57BL/6 mice were randomized to a low-fat control (CON; 10 kcal% fat) diet or DIO regimen (60 kcal% fat) for 15 weeks. DIO mice were then randomized to either remain on DIO diet (DIO-DIO) or initiate weight loss either via vertical sleeve gastrectomy (DIO-SURG, with concurrent switch to control diet) or switch to control diet without surgery (DIO-DIET). CON mice remained on the 10 kcal% fat diet throughout the study. Eight weeks later, all mice were orthotopically injected with E0771 basal-like mammary tumor cells and were euthanized when tumors from the DIO-DIO group reached 1.5cm3. Body weights were not significantly different between DIO-SURG and DIO-DIET mice but both groups weighed significantly less than DIO-DIO mice. Compared with CON mice, tumor burden was not different in DIO-SURG mice but was significantly greater in DIO-DIET mice, suggesting that surgical weight loss more effectively reverses the protumorigenic effects of obesity than a low-fat diet. We next sought to determine how the anticancer effects of calorie restricted diets compared with bariatric surgery. Another group of female C57BL/6 received DIO diet for 16 weeks, then randomized to the same CON or DIO-SURG interventions as above, or to receive one of two calorie restriction (CR) diets—chronic CR (DIO-CCR; 30% daily calorie reduction) or intermittent CR (DIO-ICR; 14% calorie reduction 5 days per week, 70% calorie reduction on 2 nonconsecutive days per week). At time of tumor collection, DIO-SURG, DIO-CCR, and DIO-ICR mice weighed significantly less than DIO-DIO mice; however, only DIO-CCR and DIO-ICR mice achieved body weights significantly lower than CON mice. Tumor weights were significantly reduced in DIO-CCR and DIO-ICR fed mice, relative to CON mice, while tumor weights of DIO-SURG mice were intermediate. Moreover, multiple linear regression indicated weight loss, irrespective of intervention, was the strongest predictor of tumor mass. Our results in a murine model of basal-like BC suggest that weight loss via CR regimens (CCR, ICR) and, to a lesser extent, bariatric surgery, mitigates the pro-tumorigenic effects of obesity.
Citation Format: Kristina K. Camp, Emily Rossi, Tori L. McFarlane, Steven Doerstling, Subreen Khatib, Elaine Glenny, Michael Coleman, Laura Bowers, Erika Rezeli, Randy J. Seeley, Alfor G. Lewis, Joel Parker, Anthony Fodor, Farnaz Fouladi, Stephen Hursting. Calorie restriction reverses the tumorigenic effects of obesity to a greater extent than bariatric surgery in a murine model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2576.