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

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.

Breast Cancer in Lean Postmenopausal Women Might Have Specific Pathological Features

“…Moreover, blocking inflammation in adipose tissue suppresses breast cancer progression (20). Such an approach, aimed at inhibiting inflammation, might be effective even for ER-negative breast cancer (21).…”

Invalidation of Microsomal Prostaglandin E Synthase-1 (mPGES-1) Reduces Diet-Induced Low-Grade Inflammation and Adiposity

“…Indeed, PGE2 was shown to exert an anti-lipolysis effect in humans and mice ( Richelsen and Pedersen, 1987 ; Ceddia et al, 2016 ) and thus proposed to facilitate adipose tissue lipid accumulation. Consistently, many works have considered the contribution of COX-2-derived PGs in obesity development, and evaluated the benefit of pharmacological or genetic COX-2 inhibition on diet-induced obesity ( Hsieh et al, 2010 ; Chan et al, 2016 ; Rossi et al, 2018 ). COX-2 and PGE2 receptor-3 (EP3) inhibitors reversed obesity-induced adipose tissues inflammation and obesity-linked complications ( Chan et al, 2016 ).…”

Novel Combination of Arsenic Trioxide (As2O3) Plus Resveratrol in Inducing Programmed Cell Death of Human Neuroblastoma SK-N-SH Cells

“…Resveratrol produces several beneficial effects, anti-aging, anti-carcinogenic, cardioprotective, and neuroprotective effects, which have been attributed to its antioxidant, anti-inflammatory, and gene-modulating properties (14). The chemopreventive and therapeutic potential of resveratrol has been demonstrated in various kinds of cancers including lung, breast, prostate and skin cancer as well as neuroblastoma (13,(15)(16)(17). Resveratrol has emerged as a potential anti-tumor agent because it has the ability to modulate the cascade signaling network involved in the proliferation and survival of cancer cells (18).…”