Abstract 597: Response of reactive oxygen species to eicosapentaenoic and calorie restriction in relation to mammary tumor prevention

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Exposure of lipid biomembranes to reactive oxygen species (ROS) results in the generation of a wide variety of lipid peroxidation products. Some of these products, including 4-hydroxy-2-nonenal (4HNE) can form protein adducts which may impact pathways associated with tumorigenesis. We have reported that calorie restriction protects against spontaneous mammary tumor development in mice and have recently shown that this is accompanied by a decrease in serum levels of lipid peroxidation products. Eicosapentaenoic acid (EPA) is known to inhibit mammary tumorigenesis; however, this type of highly unsaturated omega-3 fatty acid has also been shown to increase in vivo levels of lipid peroxidation products. In the present study, the interaction of calorie restriction and dietary EPA was investigated with respect to mammary tumor formation. Lipid peroxidation products of ROS were also measured. From 10 weeks of age MMTV-Her2/neu mice were fed a modified AIN-93M diet (10.2% kcal from fat) which had either 100% soybean oil (SO) as the fat source or a blend of EPA (72%) and SO (18%). Mice were further divided into groups which were ad libitum-fed, (AL); chronic calorie restricted (CCR, received 75% of AL) or intermittently calorie restricted (ICR, received 50% of AL for 3 weeks followed by 3 weeks at 100% of AL) until 60 weeks of age or until mammary tumor size required euthanasia. Mice were weighed and examined for mammary tumors weekly. Serum thiobarbituric acid reactive substances (TBARS) and 4-hydroxy-2-nonenal (4HNE)-protein adducts in mammary tissues were measured to assess the extent of lipid peroxidation. In both diet groups, mammary tumor incidence was highest in the AL group (SO 87%, EPA 63%). These groups also had the highest levels of serum TBARS and the AL-SO group had the highest level of mammary tissue 4HNE-protein adducts. The calorie restricted mice had lower levels of mammary tumor incidence (CCR-SO 47%, CCR-EPA 40%, ICR-SO 59%) with the lowest level in the ICR-EPA group (15%). The ICR-SO group had serum TBARS and mammary tissue 4HNE-protein adduct levels that were significantly lower than the AL-SO group (p<0.05 for both). In the EPA groups, there was no difference between the AL, CCR, and ICR groups in either serum TBARS or mammary tissue 4HNE-protein adducts. These results suggest that higher levels of lipid peroxidation products are associated with a higher incidence of mammary tumors. However, although the dietary combination of ICR and EPA resulted in the greatest amount of mammary tumor inhibition, this combination was not associated with the lowest level of lipid peroxidation products. The relationship between EPA, calorie restriction, and reactive oxygen species appears to be quite complex. 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 597. doi:1538-7445.AM2012-597