Abstract P2-05-07: Resveratrol blocks the protumorigenic effects of obesity in a postmenopausal breast cancer model

Background: In the U.S., the prevalence of obesity has reached epidemic proportions, with over two-thirds of the population being overweight and one-third being obese. Epidemiological data suggests that women who maintain a healthy weight have a lower risk of developing breast cancer and a better prognosis if diagnosed than those that are obese. Of the various breast cancer subtypes, claudin-low is associated with poor prognosis and resistance to standard chemotherapeutic regimens, Our lab has previously shown that a diet-induced obesity (DIO) regimen enhanced tumor progression and promoted the epithelial to mesenchymal transition (EMT)- and tumor–initiating cell (TIC)-associated markers in a murine claudin-low tumor model. Resveratrol is an antiinflammatory natural polyphenol that can decrease expression of markers indicative of stem cells and prevent EMT. Therefore, we hypothesized that resveratrol would impede the protumorigenic nature of obesity through its effects on EMT in a stem cell-enriched tumor model. The present study evaluated the effect of resveratrol supplementation on tumor growth in a DIO regimen in the murine M-Wnt breast cancer model. Methods: Eight-week-old ovariectomized female C57BL/6 mice were randomized (n = 15 per group) to receive one of the following three dietary regimens: control diet (10%kcal from fat), DIO regimen (60% kcal from fat), or DIO regimen supplemented with resveratrol (0.5% wt/wt). Mice consumed the experimental diets ad libitum for 6 weeks prior to orthotopic injection of 2.5×105 GFP-luciferase labeled M-Wnt murine mammary tumor cells (derived from MMTV-Wnt-1 tumor). Transplanted tumors grew for five additional weeks while diets were continued. Tumors were measured weekly with calipers and in vivo growth was monitored by the In Vivo Imaging System (IVIS). Mice were killed, serum was collected and stored at -80C and tissues were either fixed in 10% neutral-buffered saline or or flash-frozen. Results: Using the M-Wnt model of claudin-low breast cancer, we found that resveratrol supplementation significantly reduced body weight (p<0.0001), caloric intake (p<0.05) and tumor burden (weight and volume)(p = 0.021 and p = 0.007, respectively) within the DIO regimen although it had no effect on fasting glucose. Control maintained a significantly lower body fat percentage (p<0.001) than DIO regardless of resveratrol supplementation. Despite weighing significantly more (p<0.0001), mice that consumed the resveratrol-supplemented diet had comparable tumor burden to the lower calorie, control diet. Discussion: We conclude that resveratrol supplementation circumvented the protumorigenic nature of the DIO regimen equivalent to the lower calorie, lower fat control diet. Thus, dietary supplementation with resveratrol in the high-risk, obese population could break the obesity-cancer link. Keywords: epithelial to mesenchymal transition, resveratrol, mammary tumor, diet-induced obesity, stem cells. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-07.