Role of MicroRNA Regulation in Obesity-Associated Breast Cancer: Nutritional Perspectives

Abstract

Breast cancer is the most common malignancy diagnosed in women, and the incidence of breast cancer is increasing every year. Obesity has been identified as one of the major risk factors for breast cancer progression. The mechanisms by which obesity contributes to breast cancer development is not yet understood; however, there are a few mechanisms counted as potential producers of breast cancer in obesity, including insulin resistance, chronic inflammation and inflammatory cytokines, adipokines, and sex hormones. Recent emerging evidence suggests that alterations in microRNA (miRNA) expressions are found in several diseases, including breast cancer and obesity; however, miRNA roles in obesity-linked breast cancer are beginning to unravel. miRNAs are thought to be potential noninvasive biomarkers for diagnosis and prognosis of cancer patients with comorbid conditions of obesity as well as therapeutic targets. Recent studies have evidenced that nutrients and other dietary factors protect against cancer and obesity through modulation of miRNA expressions. Herein, we summarize a comprehensive overview of up-to-date information related to miRNAs and their molecular targets involved in obesity-associated breast cancer. We also address the mechanisms by which dietary factors modulate miRNA expression and its protective roles in obesity-associated breast cancer. It is hoped that this review would provide new therapeutic strategies for the treatment of obesity-associated breast cancer to reduce the burden of breast cancer.

Keywords: adipocyte; breast cancer; dietary components; microRNA; obesity.

FIGURE 1

Signaling pathways and miRNAs involved in obesity-associated breast cancer. Obesity increases the concentrations of VEGF, insulin, leptin, and inflammatory cytokines (IL-6 and TNF-α), which results in binding to its cognate cell surface receptors and activates the receptors. This activation leads to the regulation of several signaling pathways such as HIF1-α, PI3K/AKT, Ras/Raf/MAPK, JAK/STAT3, and IKK/NF-κβ. The low concentration of adiponectin abolished adiponectin signaling, leading to activation of AKT and MAPK pathways. In addition, individual or multiple miRNAs affect signaling pathways by targeting any single gene or multiple genes. As a result, this increases insulin resistance, inflammation, dysfunctional adipose tissue, adipogenesis, cell proliferation, cell survival, angiogenesis, invasion, and and metastasis, which ultimately induces the progression of breast cancer. AKT, protein kinase B; AMPK, AMP-activated protein kinase; Bcl-2, B-cell lymphoma 2; C/EBPβ, CCAAT/enhancer-binding family of proteins β ELK1, Ets-like transcription factor 1; ERK, extracellular signal-regulated kinase; ER-α, estrogen receptor alpha; FOXO1/3, forkhead box protein O1/3; HIF-1α, hypoxia-inducible factor-1α IKK, IκB kinase; IRS, insulin receptor substrate; JAK, janus family of protein kinase; miRNA, microRNA; PI3-K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; Raf, rapidly accelerated fibrosarcoma; Ras, rat sarcoma; SIRT, Sirtuin; STAT3, signal transducer and activator of transcription 3; VEGF, vascular endothelial growth factor.

FIGURE 2

The Venn diagram shows the number of uniquely regulated microRNAs between breast cancer, obesity, and obesity-associated breast cancer. The yellow arrow indicates upregulation, and the red arrow indicates downregulation.

FIGURE 3

Modulation of miRNAs by dietary agents. Dietary agents, such as vitamin D, curcumin, DIM, resveratrol, polyphenols, quercetin, linoleic acid, and proanthocyanidins, modulate miRNAs that regulate different signaling molecules involved in obesity-associated breast cancer. Abca1, ATP-binding cassette transporter 1; AKT, protein kinase B; AOAH, acyloxyacyl hydrolase; Bcl-2, B-cell lymphoma 2; C/EBP, CCAAT/enhancer-binding family of proteins; Cdc25A, cell division cycle 25A; Cdk4, cyclin-dependent kinase 4; CPT1b, carnitine palmitoyltransferase 1b; CXCL-1/-2, chemokine (C-X-C motif) ligands 1/2; DIM, 3,3′-diindolylmethane; eEF1A2, eukaryotic translation elongation factor 1α 2; FADS2, fatty acid desaturase 2; Fas, fatty acid synthase; FASN, fatty acid synthase; GLUT4, glucose transporter type 4; GSK3b, glycogen synthase kinase-3 β HMGA1, high-mobility group AT-hook 1; hTERT, human telomerase reverse transcriptase; miRNA, microRNA; myc, avian myeloblastosis; PANK1, pantothenate kinase 1; PCNA, proliferating-cell nuclear antigen; Rb1, retinoblastoma-associated protein 1; RELA, v-rel reticuloendotheliosis viral oncogene homolog A; RPS6KA6, ribosomal protein S6 kinase; SOX4, sex determining region Y box-4; Sp, specificity protein; Ucp2, uncoupling protein 2; ZBTB10, zinc finger and broad complex/tramtrack/bric-a-brac domain containing 10.