Obesity and Breast Cancer: Molecular Interconnections and Potential Clinical Applications

Abstract

Obesity is an important risk factor for breast cancer (BC) in postmenopausal women; interlinked molecular mechanisms might be involved in the pathogenesis. Increased levels of estrogens due to aromatization of the adipose tissue, inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and prostaglandin E2, insulin resistance and hyperactivation of insulin-like growth factors pathways, adipokines, and oxidative stress are all abnormally regulated in obese women and contribute to cancerogenesis. These molecular factors interfere with intracellular signaling in the mitogen-activated protein kinase and phosphatydilinositol-3-phosphate/mammalian target of rapamycin (mTOR) pathways, which regulate the progression of the cell cycle, apoptosis, and protein synthesis. In this context, structural defects of typical genes related to both BC and obesity, such as leptin, leptin receptor, serum paraoxonase/arylesterase 1, the fat mass and obesity-associated gene and melanocortin receptor 4, have been associated with a high or low risk of BC development. The early detection of these gene alterations might be useful as risk predictors in obese women, and targeting these pathways involved in the BC pathogenesis in obese women is a potential therapeutic tool. In particular, mTOR pathway deregulation concurs in both obesity and BC, and inhibition of this might disrupt the molecular interlinks in a similar manner to that of metformin, which exerts definite anticancer activity and is currently used as an antidiabetic drug with a weight-reducing property. The identification of both genetic and pharmacological implications on the prevention and management of BC is the ultimate aim of these studies.

Implications for practice: Obese women are at risk of breast cancer, but clinicians lack concrete tools for the prevention or early diagnosis of this risk. The present study, starting from the biology and the molecular defects characterizing both obesity and breast cancer, analyzed the potential molecules and genetic defects whose early identification could delineate a risk profile. Three steps are proposed that are potentially achievable in the clinical assessment of obese women, namely the evaluation of altered levels of serum molecules, the identification of genetic polymorphisms, and the study of the transcriptomic profile of premalignant lesions. Finally, the therapeutic implications of this molecular assessment were evaluated.

Keywords: Adipokines; Breast cancer; Insulin resistance; Obesity; Polymorphisms; Risk factors.

Figure 1.

Molecular breast cancer (BC)-related pathways activated in obesity. In obese patients, estrogens, insulin, IGFs, and adipokines activate pathways shown to be deregulated in BC. The estrogen receptor complex migrates to the nucleus and binds the EREs in promoters of target genes that regulate cell survival. Obesity causes increased levels of insulin, IGF-I, and IGF-II that bind the IR, IGF-IR, and a hybrid form (IR-IGF-IR), and thus activate both the RAS/MEK/MAPK and PI3K/Akt/mTOR pathways converging on S6K1. Phosphorylation of S6rp by S6K1 promotes both protein synthesis and cell proliferation. Leptin activates JAK/STAT signaling by its receptor (OB-R). Adiponectin triggers AMPK through its receptor AdipoR. AMPK phosphorylation decreases the nuclear translocation of CRTC2 that binds CREB, thus increasing the aromatase activity. These pathways, converging on NF-κB, lead to the expression of CyclD1 and c-Myc, which promotes cell survival and proliferation, as well as the secretion of VEGF and tumor angiogenesis. ROS contribute to the tumor progression, favoring the genomic instability. Abbreviations: AdipoR, adiponectin receptor; AMPK, AMP-activated protein kinase; CREB, cAMP response element-binding protein; CRTC2, CREB-regulated transcription coactivator 2; CyclD1, cyclin D1; EREs, estrogen response elements; IGF, insulin-like growth factor; IGF-IR, IGF-I receptor; IR, insulin receptor; JAK2/STAT3, janus kinase 2/signal transducer and activator of transcription 3; NF-κB, nuclear factor κB; PI3K, phosphatydilinositol-3-phosphate; ROS, reactive oxygen species; S6K1, S6 kinase-1; S6rp, S6 ribosomal protein; VEGF, vascular endothelial growth factor.

Figure 2.

Breast tissue microenvironment: stromal-epithelial interactions. Adipose tissue is a permissive environment for breast cancer (BC). Malignant epithelial cells establish close interactions with adipose fibroblasts that differentiate into mature adipocytes. BC cells produce IL-11, TNF-α, and PGE₂. IL-11 and TNF-α act as antiadipogenic cytokines and PGE₂ reinforces the aromatase expression priming PKA and PKC. PKA activates transcription factor C/EBPβ that binds the key cis-regulatory element C/EBPβS in proximity of the PI.3, and PKC activates the LRH-1 transcription factor whose binding site is located more proximal to PII. Abbreviations: IL-11, interleukin-11; LRH-1, liver receptor homolog-1; PGE₂, prostaglandin E₂; PI.3, promoter I.3 region; PII, promoter II; PKA, protein kinase A; PKC, protein kinase C; TNF-α, tumor necrosis factor-α.

Figure 3.

Drugs interfering with breast cancer (BC)- and obesity-related pathways. Drugs commonly used in BC, obesity, and diabetes interfere with intracellular signaling hyperactivation in BC. Aromatase inhibitors inhibit enzyme aromatase in the conversion of androgens, such as testosterone and androstenedione, to estrogens, such as estradiol and estrone. SERMs, such as tamoxifen, bind to estrogen receptors and induce conformational changes that inhibit the expression of estrogen-related genes. In BC cells, high levels of proinflammatory cytokines such as TNF-α, typical in obese patients, activate IKKB that phosphorylates IkB, thus activating NF-κB, composed of its subunits p50 and p65. Furthermore, phosphorylation of TSC1 by IKKB activated by mTOR kinase is involved in cell growth and angiogenesis. Drugs targeting IKKB, such as aspirin, and mTOR inhibitors, such as everolimus and rapamycin, are potentially effective as anti-BC drugs in obese women. Metformin, an antidiabetes drug that can effectively reduce body weight, activates AMPK, which phosphorylates TSC2, having an inhibitory effect on mTOR. Activation of the mTOR pathway leads to the production of VEGF, mediated by transcription factor HIF1α, which could be targeted by bevacizumab. Abbreviations: AMPK, AMP-activated protein kinase; EREs, estrogen response elements; HIF1α, hypoxia inducible factor-1α, IKKB, IkB kinase β; NF-κB, nuclear factor κB; SERMs, selective estrogen receptor modulators; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.

Figure 4.

Arbitrary BC risk grading in obese women. Considering the molecular interlinks between obesity and BC, clinical assessment of the BC risk in obese women should include three steps. The first step is to measure the serum levels of inflammatory cytokines, adipokines, insulin, IGFI, and estradiol. The second step should include the assessment of both obesity and BC-related genetic derangements such as SNPs of LEP, LEPR, PON1, FTO, MC4R, ADIPOQ, TNFα, IGFI, and PR. In the case of premalignant or suspicious lesions, the third step would include the analysis of the transcriptomic profile related to biological processes such as EMT, protein synthesis, Notch signaling, the lipid and cholesterol metabolism, inflammation, proliferation, adipokines, cell adhesion, estrogen receptor signaling, and others. Abbreviations: EMT, epithelial-to-mesenchymal transition; IGFI, insulin-like growth factor I; SNPs, single nucleotide polymorphisms.