The prevalence of obesity, an established epidemiologic risk factor for breast cancer in postmenopausal women, has dramatically increased over the past 30 years. Unfortunately, the mechanism underlying the obesity-breast cancer link in post-menopausal women, as well as the effects of cancer prevention interventions such as calorie restriction (CR) or exercise (EX), have not been well studied. CR has been shown to be an effective way to prevent tumor incidence in virtually every animal model of cancer tested. Previous studies of EX and mammary tumorigenesis in rodents have found beneficial effects of exercise when 70% VO2 max is reached. However, the mechanism by which EX alters tumor burden is unknown, and a direct comparison to CR has never been studied. We hypothesized that EX and CR exhibit anticancer effects in a mouse model of postmenopausal obesity through independent mechanisms. In our study, ovariectomized C57BL/6 female mice were administered a high-fat (HF) diet for 8 weeks to induce obesity. At week 9, the mice were randomized into 3 groups (n=15/group): obese (HF diet ad libitum); CR (30% calorie reduction relative to obese); and EX (HF diet ad libitum + treadmill exercise ~70% VO2 Max). At the end of the study (week 16) CR mice weighed significantly less than control (19.9 ± 1.9g versus 33.2 ± 5.3g, respectively) and EX mice (26.0 ± 3.2g). Both groups (38.9 ± 6.1% for CR and 33.7 ± 5.2% for EX) had significantly less percent body fat than the obese mice (57.3 ± 10.1%) with no differences in percent body fat between CR and EX mice; allowing for a direct comparison between the two interventions. CR, but not EX, improved insulin sensitivity and increased adiponectin levels compared to obese. We compared treatment-dependent changes in gene expression in visceral white adipose tissue (VWAT) and liver (key metabolic tissues) using the Affymetrix microarray platform (6 samples/group). Increased inflammation is one of the proposed mechanisms linking obesity with increased breast cancer risk. Interestingly, both CR and EX decreased the expression of inflammation-related genes in VWAT, with CR displaying a more profound effect. Also, both CR and EX decreased leptin expression (another risk factor for breast cancer) which was confirmed by serum analysis. In the liver, we found that CR and obese mice had significant differences in the expression of oxidative phosphorylation genes. EX significantly changed the expression of steroid metabolism genes compared to obese mice. Taken together, these findings suggest that CR and EX led to a reduction in inflammation-associated genes, with CR displaying a more profound effect than did EX. Also, striking differences in liver gene expression exist between the two groups, which might be responsible for the differential anti-breast cancer effects of CR and EX.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4820.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO