Obesity, Independent of p53 Gene Dosage, Promotes Mammary Tumor Progression and Upregulates the p53 Regulator MicroRNA-504

Date

2013-06-28

Authors

Ford, Nikki A.
Dunlap, Sarah M.
Wheatley, Karrie E.
Hursting, Stephen D.

Journal Title

Journal ISSN

Volume Title

Publisher

PLOS One

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 less than 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.

Description

Nikki A. Ford, Sarah M. Dunlap, Karrie E. Wheatley, Stephen D. Hursting, Department of Nutritional Sciences University of Texas at Austin, Austin, Texas, United States of America
Stephen D. Hursting, Department of Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas, United States of America

LCSH Subject Headings

Citation

Ford NA, Dunlap SM, Wheatley KE, Hursting SD (2013) Obesity, Independent of p53 Gene Dosage, Promotes Mammary Tumor Progression and Upregulates the p53 Regulator MicroRNA-504. PLoS ONE 8(6): e68089. doi:10.1371/journal.pone.0068089