Resveratrol inhibits obesity-associated adipose tissue dysfunction and tumor growth in a mouse model of postmenopausal claudin-low breast cancer

Emily L. Rossi, Subreen A. Khatib, Steven S. Doerstling, Laura W. Bowers, Melissa Pruski, Nikki A. Ford, Randolph D. Glickman, Mengmeng Niu, Peiying Yang, Zhengrong Cui, John Digiovanni, Stephen D. Hursting

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Adipose tissue dysregulation, a hallmark of obesity, contributes to a chronic state of low-grade inflammation and is associated with increased risk and progression of several breast cancer subtypes, including claudin-low breast tumors. Unfortunately, mechanistic targets for breaking the links between obesity-associated adipose tissue dysfunction, inflammation, and claudin-low breast cancer growth have not been elucidated. Ovariectomized female C57BL/6 mice were randomized (n = 15/group) to receive a control diet, a diet-induced obesity (DIO) diet, or a DIO + resveratrol (0.5% wt/wt) diet. Mice consumed these diets ad libitum throughout study and after 6 weeks were orthotopically injected with M-Wnt murine mammary tumor cells, a model of estrogen receptor (ER)-negative claudin-low breast cancer. Compared with controls, DIO mice displayed adipose dysregulation and metabolic perturbations including increased mammary adipocyte size, cyclooxygenase-2 (COX-2) expression, inflammatory eicosanoid levels, macrophage infiltration, and prevalence of crown-like structures (CLS). DIO mice (relative to controls) also had increased systemic inflammatory cytokines and decreased adipocyte expression of peroxisome proliferator-activated receptor gamma (PPARγ) and other adipogenesis-regulating genes. Supplementing the DIO diet with resveratrol prevented obesity-associated increases in mammary tumor growth, mammary adipocyte hypertrophy, COX-2 expression, macrophage infiltration, CLS prevalence, and serum cytokines. Resveratrol also offset the obesity-associated downregulation of adipocyte PPARγ and other adipogenesis genes in DIO mice. Our findings suggest that resveratrol may inhibit obesity-associated inflammation and claudin-low breast cancer growth by inhibiting adipocyte hypertrophy and associated adipose tissue dysregulation that typically accompanies obesity.

Original languageEnglish (US)
Pages (from-to)393-407
Number of pages15
JournalMolecular Carcinogenesis
Volume57
Issue number3
DOIs
StatePublished - Mar 2018

Keywords

  • diet-induced obesity
  • mammary tumor
  • resveratrol

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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    Rossi, E. L., Khatib, S. A., Doerstling, S. S., Bowers, L. W., Pruski, M., Ford, N. A., Glickman, R. D., Niu, M., Yang, P., Cui, Z., Digiovanni, J., & Hursting, S. D. (2018). Resveratrol inhibits obesity-associated adipose tissue dysfunction and tumor growth in a mouse model of postmenopausal claudin-low breast cancer. Molecular Carcinogenesis, 57(3), 393-407. https://doi.org/10.1002/mc.22763