P2-03-01: Genetic Reduction of Circulating Insulin-Like Growth Factor (IGF)-1 Differentially Impacts the Effects of Diet-Induced Obesity and Calorie Restriction on Mammary Tumor Progression.
Authors: NA Ford, NP Nunez, SN Perkins, SD Hursting
Journal: Cancer Research (2011)

Abstract Background: Epidemiological evidence suggests that obesity worsens breast cancer prognosis in pre- and postmenopausal women. Previously we demonstrated that diet-induced obese (DIO) mice and rats have higher circulating levels of IGF-1 and enhanced mammary tumor burden compared to normoweight controls. In contrast, we have found in several mouse models that a 30% calorie restricted (CR) diet regimen reduced serum IGF-1 levels and decreased mammary tumor growth. The present study investigated the effects of CR and DIO on mammary tumor growth in mice with normal serum levels of IGF-1 (wild-type) or mice with reduced circulating levels of IGF-1 (LID). Our goal was to identify new targets and strategies (with a focus on the IGF-1 pathway) for breaking the obesity-breast cancer link, which is important given the high prevalence of obesity in the U.S., and the strong association between obesity and breast cancer. Materials and Methods: Virgin female liver-specific IGF-1-deficient (LID) and wild-type (FVB/NCr) mice (10-12 weeks of age) were randomized (n=10-14 per group) to receive: control diet (modified AIN-76A), a 30% CR regimen, or a DIO regimen (60 kcal% fat diet). Mice consumed the experimental diets for 11 to 15 weeks prior to orthotopic injection (4th mammary fat pad) of Met-1fvb2murine mammary tumor cells derived from a polyoma middle-T antigen transgenic mouse mammary tumor. Transplanted tumors were allowed to grow for 4 weeks and tumor volume was measured by electronic calipers biweekly. Mice were then killed, serum was collected and stored at −80C, and tumors were excised, weighed and either formalin-fixed, paraffin-embedded or flash-frozen. Results: Using the LID mouse model of IGF-1 deficiency, this study established that decreased circulating IGF-1 (relative to wildtype mice) dramatically reduces Met-1fvb2 mammary tumor growth regardless of diet treatment (P=0.034). We also showed in LID mice that CR (44 +/− 15.6 mm3), relative to control diet (89 +/− 33 mm3) has no significant effect on Met-1fvb2 tumor growth, suggesting nearly all of the suppressive effects of CR on tumor growth (at least in the Met-1fvb2 model), can be explained by reduced systemic IGF-1. In contrast, while most of the DIO effect on tumor growth was ablated in the LID mice (332 +/− 104 mm3) vs. wild-type mice (3130 +/− 421 mm3), tumor growth in LID/DIO mice was significantly higher than LID/control mice (89 +/− 33, P=0.006) despite no change in IGF-1 levels, suggesting that a mechanism independent of IGF-1 contributes to some of the effects of DIO on Met-1fvb2 mammary tumor growth. Within LID mice, serum insulin, resistin and adiponectin were not modified by the CR or DIO diet. Discussion: We conclude that components of the IGF-1 pathway represent promising mechanistic targets for mimicking the anticancer effects of CR and breaking the obesity-breast cancer link. However, there are likely other mechanisms independent of IGF-1 that contribute to the breast tumor enhancing effects of DIO and that need to be defined. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-03-01.