title: Obesity, independent of p53 gene dosage, promotes mammary tumor progression and upregulates the p53 regulator microRNA-504.
abstract: 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.
authors.affiliation: Department of Nutritional Sciences University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Nikki A
authors.initials: NA
authors.lastname: Ford
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Dunlap
authors.forename: Karrie E
authors.initials: KE
authors.lastname: Wheatley
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hursting
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D004032:Diet; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D009765:Obesity / Q000150:complications* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics*; D051155:Wnt1 Protein / Q000235:genetics
chemical_list: D047628:Estrogen Receptor alpha; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse