Effects of calorie restriction and exercise on gene expression profiles in mammary glands of p53+/- MMTV-Wnt-1 transgenic mice.

B171

Previously, we have seen that calorie restriction (CR) can delay mammary tumorigenesis both in p53 wild type (p53+/+) and p53 heterozygous (p53+/-) MMTV Wnt-1 (Wnt-1) transgenic mice. In contrast, treadmill exercise (EX) of a moderate intensity hastened tumorigenesis in p53+/-:Wnt-1 mice. We hypothesized that CR and EX act through different mechanisms in this mouse model and sought to determine the effects of both reduced p53 gene dosage and exercise or CR interventions in this context on global mammary gene expression in Wnt-1 transgenic mice. Thirteen-week-old female p53+/-:Wnt-1 mice were randomly assigned to receive either control diet (ad libitum) with no exercise, control diet plus a moderate treadmill exercise regimen, or a 40% CR regimen (with no exercise). A comparison group of p53+/+:Wnt-1 mice fed control diet ad libitum was also included. At the end of the six-week treatment period, gene expression profiles of mammary tissue from 3-5 tumor-free mice/group were compared using Affymetrix 430 2.0 GeneChips and analyzed using Affymetrix MAS 5.0 software. Comparison of the p53+/+: Wnt-1 and p53+/-:Wnt-1 mice revealed 529 transcripts that were significantly altered (p<0.01, â-¥ 2-fold). The majority of these genes were down-regulated in p53+/-:Wnt-1 compared to the p53+/+: Wnt-1 control and represented processes including protein synthesis and trafficking, molecular transport, and nucleic acid metabolism and processing. CR reversed virtually all of the significant gene expression changes seen in response to reduced p53 gene dosage and also altered some unique genes not affected by p53 status. In contrast, only 35 genes were significantly altered by EX in comparison to the p53+/-:Wnt-1 control, and these alterations included genes involved in immune response. Our findings suggest that CR delays mammary tumorigenesis in this model by preventing many of the alterations caused by reduced p53 gene dosage, as well as through p53-independent mechanisms. In contrast, EX is acting through very different mechanisms than CR and is unable to reverse changes due to reduced p53 gene dosage. Further analysis of specific gene changes is ongoing to help resolve how CR acts to prevent cancer and EX does not in this model of mammary tumorigenesis.