P4-05-02: Early Developmental Exposures to a High Carbohydrate/High Fat Diet Affect Glucose Metabolism and Mammary Cancer Susceptibility.
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AbstractBackgroundThe obesity epidemic in the U.S. has substantially increased the number of people with altered glucose metabolism. Alterations in metabolic programming, resulting from early exposures can affect development, metabolism as well as propensity to later diseases, including cancer. The Warburg effect describes a mechanism by which diet-induced hyperglycemia and hyperinsulinemia can contribute to cellular transformation. To investigate the effect of a hyperinsulinemia-, hyperglycemia-inducing (HI/HG) diet on metabolic programming and susceptibility to mammary cancer, we exposed developing mouse pups during three developmental stages: gestation, lactation and post-weaning.Materials and Methods: Female SENCAR mice were fed either a mildly restricted, defined, chow like control diet (DR) or a HI/HG, high sucrose/high fat (HS/HF) diet. At 14 weeks, both DR and HS/HF fed female mice were bred and the resulting offspring were randomized into 8 groups to model all combinations of gestational, lactational and post-weaning dietary exposures. Body weights (BW) were recorded weekly and Glucose Tolerance Tests (GTTs) were conducted on the female offspring at 1012 weeks of age. Starting at 79 weeks of age, mice received 20 mg/day of DMBA or vehicle by daily gavage to induce mammary carcinogenesis.Results: Animals in the DR/DR/DR (gestational diet/nursing diet/post-weaning diet) and HS/DR/DR groups had the lowest average BW and retained normal response to glucose, while mice in the DR/HS/HS and HS/HS/HS groups had the highest average BW. Interestingly, animals born to DR-fed and nursed by HS/HF mothers and weaned onto a HS/HF diet (DR/HS/HS) were the most glucose intolerant. In response to DMBA, animals in the different dietary regimens partitioned into high, moderate or low mammary tumor incidence groups. Mice fed consistent diets throughout gestation, lactation and post-weaning (DR/DR/DR or HS/HS/HS) had intermediate tumor incidence. However, mice exposed to DR during gestation and/or lactation and then switched to a HS/HF diet at weaning had the highest tumor incidence and shortest latency. Mice exposed to a HS/HF diet during gestation and/or lactation and then switched to a DR diet at weaning had the fewest mammary tumors and longest latency.Conclusion: Our data indicate that substantial changes in the type and abundance of calories during gestation and/or lactation had long-lasting impacts on BW, glucose metabolism, and mammary tumorigenesis. Since BW did not consistently correlate with GTT results, the effects of dietary manipulation on obesity and glucose metabolism appear to be distinguishable. Results also indicate that diet-induced changes in the glucose metabolism of the mother profoundly affected tumor susceptibility in the exposed female offspring. These findings support the contention that rising levels of obesity, metabolic syndrome, and diabetes, especially in young individuals, may contribute to the increasing incidence of early onset breast cancer.Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-05-02.
