Abstract 4321: The pro-tumorigenic effects of obesity are reversed by severe weight loss via chronic or intermittent calorie restriction but not weight normalization via a low-fat diet

Background: Breast cancer outcomes in both pre- and postmenopausal women are negatively impacted by obesity, but the reversibility of these pro-cancer effects via weight loss has not been well established. We examined how weight loss via four different dietary interventions affects mammary tumor progression in a mouse model of chronic obesity and pre-menopausal basal-like breast cancer. Methods: Six week old C57BL/6 mice were randomized to a control (Con, 10% kcal from fat) or diet-induced obesity (DIO, 60% kcal from fat) regimen and maintained on these diets for 15 weeks. DIO mice were then randomized to remain on DIO diet (Obese) or begin one of four weight loss regimens: low-fat control (formerly obese, FOb), high-carb 30% calorie-restricted (HCCR), low-carb 30% CR (LCCR), or intermittent energy restriction (IER). IER mice received a 14% CR diet 5 days/week and a 70% CR diet on 2 non-consecutive days/week, such that their average daily kcal intake and macronutrient distribution was equivalent to the LCCR group. The Con mice received the same control diet through the end of the study to maintain a normal weight. Mice were orthotopically injected with E0771 mouse mammary tumor cells at week 25. All mice were euthanized when one tumor reached 1.5 cm in diameter. Results: At study endpoint, Obese mice had a higher average body weight and body fat percentage in comparison to all other diet groups. These phenotypic measures were statistically equivalent in Con and FOb mice, indicating that the FOb mice had returned to a normal weight and body fat percentage, but they were significantly lower in the 3 CR groups. The CR mice all lost and then maintained an equivalent amount of weight following the diet switch at 15 weeks, regardless of the diet timing or macronutrient distribution. Tumor volume and weight at sacrifice were significantly greater in the Obese mice relative to Con mice and all CR mice, but not FOb mice, despite their weight loss to Con levels. In contrast, tumors in the HCCR and IER, but not LCCR, mice were significantly smaller than Con. Serum insulin and leptin levels were statistically equivalent in Con, FOb, HCCR, LCCR, and IER, but serum insulin-like growth factor 1 remained significantly elevated in FOb mice, with levels statistically equivalent to Obese mice. Conclusions: These results suggest that weight normalization via a low-fat control diet does not reverse the mammary tumor-promoting effects of chronic obesity. However, severe weight loss through various forms of calorie restriction successfully reverses these effects. An improved understanding of the energy responsive mechanisms mediating the anticancer effects of calorie restriction in obese mice may lead to the identification of new intervention targets and strategies to reduce the impact of obesity on breast cancer outcomes. Citation Format: Laura W. Bowers, Emily L. Rossi, Meghana G. Shamsunder, Stephen D. Hursting. The pro-tumorigenic effects of obesity are reversed by severe weight loss via chronic or intermittent calorie restriction but not weight normalization via a low-fat diet. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4321.