Abstract
Introduction: Nutrition can have a profound effect on breast cancer inhibition and growth. We have focused on two dietary interventions that separately prevent mammary tumorigenesis, eicosapentaenoic acid (EPA), an ω-3 fatty acid, and intermittent calorie restriction (ICR), as we recently reported that multiple periods of intermittent caloric restriction (ICR) were superior for inhibition of mammary tumor (MT) formation compared to chronic calorie restriction. Here we assessed whether combining two interventions, EPA consumption and ICR, would achieve even greater inhibition of breast cancer formation than either alone.
Methods: Four groups of MMTV-HER-2/neu transgenic mice that are genetically programmed to develop mammary tumors were utilized. From 10 weeks of age half of the mice were fed a diet with fat derived from soy oil and the other half consumed a diet with 71.75% of fat calories from EPA. Mice were further divided into ad libitum (AL) or intermittent caloric restricted (ICR) groups. AL groups (soy oil and EPA) received unrestricted access to their diets. 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. Mice were weighed weekly and carefully examined for mammary tumors. The 6 week cycle of restriction/refeeding was maintained until the mice were 55 weeks or were euthanized due to MTs.
Results: The Ad Lib Soy and Ad Lib EPA groups ate similar amounts and gained weight at similar rates. The body weights of the ICR Soy and ICR EPA groups were not significantly different from each other but were significantly lower than the Ad Lib mice. The tumor free period was shortest in the AL Soy with increasingly long tumor free periods for the Ad Lib EPA, ICR Soy and the ICR EPA groups. The tumor free period of the ICR EPA group was significantly longer than all the other groups (ICR EPA vs Ad Lib Soy P<0.002, vs Ad Lib EPA P<0.004, vs ICR Soy P<0.007). ICR EPA survival until terminal end point was also significantly different than for all other groups (ICR EPA (100%) vs Ad Lib Soy (47%) P<0.0006, vs Ad Lib EPA (60%) P<0.004, vs ICR Soy (74%) P<0.03). The average week to palpable tumor (7 mm) was 43 weeks for the Soy fed group and 49.3 weeks for the EPA fed group. The percentage of mice that were tumor free at the end of the study and the tumor burden per animal were significantly different. Cohorts of Ad Lib Soy and Ad Lib EPA mice were anesthetized and serum obtained 17 weeks (25 weeks of age) or 29 weeks (37 weeks of age) after enrollment. All mice were tumor free at the time of collection and there were three mice from each group (12 mice total). An array based scheme was performed in triplicate to examine the serum levels of 308 different proteins. A number of proteins were differentially regulated by consumption of EPA compared to Soy oil. Of particular interest to us was the fact that several proteins that are part of the NFκB pathway were down-regulated at both the ages of 25 and 37 weeks by EPA.
Conclusions: These results illustrate that mammary tumor inhibition is significantly increased when ICR and EPA are combined as compared to either intervention alone or no intervention. It also identifies the NFκB pathway as a potential pathway of interest for inhibition of mammary tumor formation. Understanding how this pathway is affected may aid in the development of drugs that could be used for breast cancer prevention.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):B63.
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