Obesity, prevalent in >35% of US women, is an established risk and progression factor for postmenopausal breast cancer, and strategies to break the obesity-breast cancer link are urgently needed. Approximately 30% of breast cancers carry p53 tumor suppressor gene alterations; however, the effects of obesity on breast cancer progression in relation to p53 gene dosage are unclear. Using murine models of postmenopausal breast cancer, we characterized the interactive effects of diet-induced obesity (DIO) and p53 gene dosage on mammary tumor growth and associated p53-related regulatory mechanisms. Ovariectomized C57BL/6 mice were randomly assigned to receive a DIO or control diet, and (at 10 weeks) orthotopic injection of MMTV-Wnt-1 p53(+/-) or MMTV-Wnt-1 p53(+/+) mammary tumor cells (n = 20 mice per diet and genotype group). DIO and control diets produced distinct phenotypes (mean percent body fat at 10 weeks: 57% and 39%, respectively, P<0.001). Regardless of phenotype, time to first palpable tumor was 57% less for Wnt-1 p53(+/-) than Wnt-1 p53(+/+) tumors. Regardless of tumoral p53 genotype, DIO (relative to control) increased tumor burden, tumor cell proliferation (Ki-67), severity of tumor pathology, local tissue invasion, epithelial-to-mesenchymal transition (EMT) programming, and tumoral microRNA-504 (a negative regulator of p53) expression; and suppressed p53, p21, and estrogen receptor-alpha protein expression. These findings in murine models of postmenopausal breast cancer suggest that obesity may augment procancer effects related to p53 gene alterations. Furthermore, microRNA-504, an obesity-responsive negative regulator of p53 and putative EMT regulator, may represent a novel molecular target for breaking the obesity-breast cancer link.