Eicosapentaenoic Acid Increases Mammary Tumor Inhibition Of Intermittent Calorie Restriction And Regulates Adipokines

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL It has become clear that the use of combination therapies for prevention of breast cancer may be more efficacious than individual therapies. Therefore, we combined two different interventions which had each been shown alone to inhibit mammary tumorigenesis but had not been tested in combination. The first intervention was consumption of the omega-3 fatty acid eicosapentaenoic acid (EPA) which is found in fish oil and the second intervention was calorie restriction. We utilized six groups of MMTV-Her2/neu mice as a model for human breast cancers which over express Her2/neu. Starting at 10 weeks of age half of the mice were fed a control diet composed of a modified AIN-93M formula with fat derived from soy oil. The other half consumed a diet with 71.75% of fat calories from EPA. Mice were further divided into ad libitum (AL), chronic calorie restricted (CCR) or intermittent caloric restricted (ICR) groups. AL groups (Control and EPA) received unrestricted access to their diets. CCR groups were given 75% of the total calories that the AL age-matched groups consumed. ICR groups were fed calories equal to 100% of the AL age-matched groups for three weeks followed by three weeks of calories equal to 50% of the AL age-matched groups. The 6 week cycles of restriction and refeeding were maintained until the mice were 60 weeks of age or were euthanized due to mammary tumors (MTs). MT incidence was lowest in the ICR-EPA group (15%) and highest in the AL-Con group (87%) while the AL-EPA, CCR-Con, CCR-EPA and ICR-Con had MT incidence rates of 63%, 47%, 40% and 59%, respectively The average survival until terminal end point was also longest in the ICR-EPA group at 59.2 weeks and shortest in the AL-Con group at 52.6 (P<0.0002). The average tumor burden was 0.98 grams for ICR-EPA mice and 1.78 grams for AL-Con mice but due to the very small number of MTs in the ICR-EPA group this was not a significant difference. Histopathology showed no significant difference in tumor grades between the groups. To better understand the effects of the interventions we examined serum for alterations in adipokines and growth factors. We found that EPA consumption dramatically reduced the levels of leptin (P<0.02) and increased the levels of adiponectin in the AL mice (P<0.001) but did not significantly alter animal weights at 25 weeks of age. Calorie restriction was also able to significantly decrease serum leptin levels and increase serum adiponectin levels. Serum IGF-I was significantly reduced by calorie restriction with the ICR-Con having the lowest level. The presence of EPA in the diet did not significantly change the levels of IGF-I. These results illustrate that MT inhibition is significantly increased when ICR and EPA are combined as compared to either intervention alone or no intervention. This effect may be related to alterations in serum growth factors and adipokines. Support: Susan G.Komen for the Cure and The Hormel Foundation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 585. doi:1538-7445.AM2012-585