Role of adipokines and cytokines in obesity-associated breast cancer: therapeutic targets

Abstract

Obesity is the cause of a large proportion of breast cancer incidences and mortality in post-menopausal women. In obese people, elevated levels of various growth factors such as insulin and insulin-like growth factors (IGFs) are found. Elevated insulin level leads to increased secretion of estrogen by binding to the circulating sex hormone binding globulin (SHBG). The increased estrogen-mediated downstream signaling favors breast carcinogenesis. Obesity leads to altered expression profiles of various adipokines and cytokines including leptin, adiponectin, IL-6, TNF-α and IL-1β. The increased levels of leptin and decreased adiponectin secretion are directly associated with breast cancer development. Increased levels of pro-inflammatory cytokines within the tumor microenvironment promote tumor development. Efficacy of available breast cancer drugs against obesity-associated breast cancer is yet to be confirmed. In this review, we will discuss different adipokine- and cytokine-mediated molecular signaling pathways involved in obesity-associated breast cancer, available therapeutic strategies and potential therapeutic targets for obesity-associated breast cancer.

Keywords: AMP-activated protein kinase; AMPK; Adiponectin; BMI; Breast cancer; C/EBPα; CCAAT/enhancer binding protein-α; CDK; CLS; COX-2; Cytokines; EGCG; ERK; ERα; GSK-3β; HB-EGF; HER-2; HIF-1α; IFNs; IGF binding proteins; IGF-1R; IGFBPs; IGFs; ILs; JAK2; JNK; Janus kinase-2; LDL; Leptin; MAPK; NFκB; NSAIDs; Obesity; PARP; PDGF-BB; PEG-LPrA2; PFS; PPARα; SHBG; SOCS3; STAT3; TNF-α; VEGF; VEGF-R2; bFGF; basic fibroblast growth factor; body mass index; c-Jun N-terminal kinase; crown-like structure; cyclin-dependent kinase; cyclooxygenase-2; epigallocatechin-3-gallate; estrogen receptor-α; extracellular signal-regulated kinase; glycogen synthase kinase-3β; hTERT; heparin-binding epidermal growth factor-like growth factor; human epidermal growth factor receptor-2; human telomerase reverse transcriptase; hypoxia-inducible factor-1α; insulin-like growth factor-1 receptor; insulin-like growth factors; interferons; interleukins; low-density lipoprotein; mTOR; mammalian target of rapamycin; mitogen-activated protein kinase; non-steroidal anti-inflammatory drugs; nuclear factor kappa-B; pegylated leptin peptide receptor antagonist 2; peroxisome proliferator-activated receptor-α; platelet-derived growth factor subunit B homodimer; poly (ADP-ribose) polymerase; progression-free survival; sex hormone binding globulin; signal transducer and activator of transcription-3; suppressor of cytokine signaling-3; tumor necrosis factor-α; vascular endothelial growth factor; vascular endothelial growth factor receptor-2.