Exercise and p53 gene dosage effects on gene expression profiles in mammary glands of MMTV-Wnt-1 transgenic mice.

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Previously, we have seen that calorie restriction (CR) can delay mammary tumorigenesis in p53 heterozygous (p53^+/-) MMTV-Wnt-1 (Wnt-1) transgenic mice, while treadmill exercise of a moderate intensity hastens tumorigenesis in these same mice. We hypothesized that exercise may be detrimental due to the p53 deficiency, and therefore sought to determine the global changes in mammary gland gene expression in p53^+/+ and p53 ^+/- mice with and without exercise. We further examined whether there was an interaction between exercise and p53 genotype. Thirteen-week-old female p53^+/+:Wnt-1 and p53^+/-: Wnt-1 transgenic mice were singly housed and randomly assigned to either moderate exercise treadmill training or non-exercise control groups. 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 R, Bioconductor, and Ingenuity Pathway analysis software. There was a significant interaction between p53 status and exercise for 775 genes (p<0.001; ≥ 2-fold expression). Network analysis indicated that many of the genes identified in the interaction were involved in protein synthesis and trafficking, and molecular transport. Eighty-five and 182 genes were differentially expressed based on exercise and p53 status, respectively. These genes were related to cell cycle, differentiation, and proliferation; however, the specific genes that were up-or down-regulated differed. This data suggests that exercise affects mammary gland gene expression differentially based on p53 status. Ongoing analysis of specific gene changes will serve to clarify these findings.