The adult prevalence of obesity in the United States exceeds 30% and obesity is associated with increased cancer risk and poor prognosis, including postmenopausal breast cancer. p53 is a tumor suppressor gene that responds to diverse cellular stress including DNA damage, oxidative stress and hypoxia. p53 is mutated in most human cancers, including postmenopausal breast cancer, and is involved in the regulation of lipogenic enzymes. However, the links between p53 and obesity in postmenopausal breast cancer are poorly understood. Here we test the hypothesis that the effect of obesity on mammary tumor growth is impacted by p53 status. The aim of this study was to determine how p53-deficient mammary tumor cells (relative to p53 wild-type cells) respond to obesity-driven tumor growth. To test this hypothesis, we used ovariectomized (OVX) C57BL/6 mice randomized to a control diet (n=40) or a diet-induced obesity (DIO) regimen (n=40) for 10 weeks. At the time, DIO mice were approximately 40% heavier (p<0.001) and had 45% greater adiposity (p<0.001) than control mice. Mice were then injected (in the 4th mammary fat pad) with either p53-deficient (p53+/-) or p53 wild-type (p53+/+) MMTV-Wnt-1 mammary tumor cells. Mice were monitored for tumor growth, killed when moribund, and tumors were collected at study end point. We found an interaction between diet and p53 status, with p53+/+ Wnt-1 tumors grown in DIO mice developing the more aggressive morphology compared to p53+/+ Wnt tumors in control mice while the observation was not seen in p53+/- Wnt tumors. From histopathological analysis we also discovered that the DIO regimen promotes local invasion of mammary tumor cells and alters the morphology of MMTV-Wnt-1 p53+/+ mammary tumors. Specifically, p53+/+ Wnt tumors grown in DIO mice displayed disorganized ductal structures characteristic of p53+/- tumors grown in control mice, and DIO exacerbated this aberrant morphology in p53+/- Wnt tumors. Moreover, immunohistological analyses showed that DIO reduces p53 protein expression while elevating Ki-67 expression only in the p53+/+ Wnt mammary tumors. These results suggest that p53 and DIO have interactive effects on mammary tumor growth, as p53+/+ Wnt tumors growing in DIO mice resulted in higher tumor grade similar to p53+/- Wnt tumors. / text