Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment
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Amitabha Ray
Abstract
Obesity is associated with the risk of several health disorders including certain cancers. Among obesity-related cancers, postmenopausal breast carcinoma is a well-studied one. Apart from an increase in certain types of lipids in obesity, excess adipose tissue releases many hormone-like cytokines/adipokines, which are usually pro-inflammatory in nature. Leptin is one of such adipokines and significantly linked with the intracellular signaling pathways of other growth factors such as insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2). In general, HER2 is overexpressed in roughly 30% of breast carcinomas; its presence indicates aggressive tumor behavior. Conversely, HER2 has certain effects in normal conditions such as differentiation of preadipocytes, cardiovascular health and vitamin D metabolism. HER2 has no known endogenous ligand, but it may form dimers with other three members of the epidermal growth factor receptor (EGFR) family and can activate downstream signaling pathways. Furthermore, HER2 is intimately connected with several enzymes, e.g. fatty acid synthase (FASN), phosphatidylinositol 3-kinase (PI3K), AKT and mechanistic target of rapamycin (mTOR), all of which play significant regulatory roles in lipogenic pathways or lipid metabolism. In obesity-related carcinogenesis, characteristics like insulin resistance and elevated IGF-1 are commonly observed. Both IGF-1 and leptin can modulate EGFR and HER2 signaling pathways. Although clinical studies have shown mixed results, the behavior of HER2+ tumor cells including HER2 levels can be altered by several factors such as obesity, leptin and fatty acids. A precise knowledge is useful in new therapeutic approaches against HER+ tumors.
Introduction
Currently one of the most important public health problems throughout the world is obesity, which is associated with the risk of a number of diseases such as type 2 diabetes, cardiovascular disorders and certain cancers. According to the World Health Organization’s (WHO) report, 39% of adults were overweight [body mass index (BMI) ≥ 25.0] worldwide in 2014; of these 13% were obese (BMI ≥ 30.0). The etiology of overweight or obesity is highly complex and linked with multifactorial aspects such as genetic, lifestyle and socioeconomic factors. However, it is generally agreed that an excessive adipose tissue mediates a chronic low-grade inflammation, which possibly induces the disease processes. In obesity, a wide range of dysregulation in systemic metabolism has been observed, e.g. hyperglycemia, dyslipidemia, hyperinsulinemia, abnormal levels of sex hormones and adipokines [1], [2]. Many components of these metabolic pathways are used in clinical laboratories in order to assess different obesity-related health conditions.
Adipose tissue biosynthesizes several hormone-like cytokines or adipokines [3]. In this regard, the adipose tissue can be considered as an endocrine organ. Nevertheless, the majority of these adipokines are pro-inflammatory in nature. One of the important pro-inflammatory adipokines is leptin. In normal healthy condition, leptin plays a key role as an anorexigenic (appetite suppressant) hormone and in energy homeostasis. In general, leptin functions through leptin receptors (Ob-R); at least six isoforms of Ob-R exist. Probably, the long transmembrane isoform Ob-Rb is important in both physiological and pathological effects of leptin [4]. A number of intracellular signaling molecules, e.g. Janus kinase (JAK), signal transducer and activator of transcription (STAT), phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK), are associated with leptin-regulated pathways [3], [5].
Leptin is closely linked with several growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor 21 (FGF21), and insulin-like growth factor-1 (IGF-1) [5], [6], [7] (Table 1) [1], [4], [8], [9], [10], [11]. A study on human subjects detected an increased gene expression of leptin and IGF-1 in the subcutaneous fat of the obese group, while the expression of IGF-1 in the visceral fat was higher in the control group (non-obese cholecystectomy cases) [12]. Similar findings were revealed by another report that observed higher circulating concentrations of leptin and IGF-1 in excess abdominal fat [13]. In the experimental animals (mice) administration of recombinant leptin induced a three-fold increase in liver-derived IGF-1 [7]. Moreover, an in vitro study showed that the addition of leptin increased the expression of IGF-1 in MDA-MB-361 and SK-BR-3 breast cancer cell-lines [14]. Alternatively, stimulation with IGF-1 promoted Ob-R phosphorylation in MDA-MB-231, MCF-7, BT474, and SK-BR-3 breast cancer cell-lines [15].
A short overview of commonly studied cytokines/growth factors in obesity.
| Category | Cytokine or growth factor | Chiefly produced by | Receptor | Function |
|---|---|---|---|---|
| Inflammation | Interleukin-6 (IL-6) [1], [8] | Many cell types such as immune cells, fibroblasts, and endothelial cells | Two forms: the transmembrane glycoprotein IL-6R (gp80) and soluble sIL-6R. The ligand-receptor complex binds to transmembrane gp130, which leads to signal transduction | Pleiotropic effect on inflammation, immune response, and regulation of metabolism |
| Inflammation | Tumor necrosis factor-α (TNF-α) [1], [9] | Macrophages; other cells like T-lymphocytes and natural killer (NK) cells | TNFR-1: ubiquitous, possesses the death domain; TNFR-2: present mainly in immune cells, higher affinity | Multifunctional including inflammation, immunity and apoptosis |
| Insulin resistance | Insulin-like growth factor-1 (IGF-1) [1], [10] | Hepatocytes; other cells throughout the body | IGF-1 can bind to its receptor (IGF1R), and also to the insulin receptor (IR), and IR/IGF1R hybrid receptor | Performs like anabolic hormone, along with paracrine and autocrine properties |
| Adipokine | Leptin [4], [11] | Adipocytes; other cells including gastric and mammary epithelium | Similarity with the class I cytokine receptor family (like receptor for IL-6). At least 6 isoforms including the long Ob-Rb and soluble Ob-Re forms | Acts like a pleiotropic hormone, and normally plays a key role in energy balance |
There is a complex relationship between IGF-1 and obesity or obesity-related diseases [16], [17], [18]. However, regarding the pathogenesis of obesity-related cancers, a plausible explanation has been proposed [18], [19], [20]. The inflammatory situation in obesity perhaps creates a state of insulin resistance where cells cannot utilize glucose appropriately due to the defective response to insulin. To overcome this condition, the pancreas produces more insulin, which causes hyperinsulinemia, alterations in IGF-binding proteins (IGFBPs), and increased biosynthesis of IGF-1 from the liver. Finally, in obesity, several biological components such as elevated bioavailable IGF-1, pro-inflammatory adipokines like leptin, and angiogenic factors like VEGF play a key role in the pathogenesis of cancer [18], [19], [20].
Like IGF-1, another widely studied growth stimulating component is epidermal growth factor receptor (EGFR) and its ligands. For a long time, a number of studies have noticed a crosstalk between the IGF-1 and EGFR signaling pathways [21], [22], [23]. Their synergistic interactions are thought to be associated with the acquired resistance to EGFR-tyrosine kinase inhibitors like gefitinib [22]. Both of these mitogenic signaling pathways are potent regulators of cellular proliferation and survival. In a study of colorectal cancer cases with regional lymph node involvement, coexpression of the IGF-1 receptor (IGF1R) and EGFR was present in more than 75% of tumors [24]. Moreover, the EGFR and IGF1R crosstalk has been demonstrated in other cancers such as pancreatic cancer and breast cancer [25], [26], [27], [28]. Interestingly, in pancreatic cancer, cases with high membrane expression of IGF1R and cytoplasmic detection of EGFR were correlated with poor prognosis [25], [26]. In another study, Morgillo et al. [29] found that most non-small cell lung cancer (NSCLC) tissues with EGFR overexpression had associated high levels of IGF1R expression. In brain metastases originating from lung cancer, a shorter median survival was recorded in cases with high expression of phosphorylated IGF1R and EGFR mutations [30]. Furthermore, Moore et al. [31] documented the IGF1R and EGFR crosstalk as one of the potential mechanisms for obesity enhanced tumor promotion.
The EGFR and its family
Members of EGFR or erythroblastic leukemia viral oncogene homolog B (ErbB) or human epidermal growth factor receptor (HER) family, which are transmembrane glycoproteins, possess tyrosine kinase activity. Among four members of this family (HER1-4), EGFR and HER2 or neuro/glioblastoma derived oncogene homolog (neu) [or cellular erythroblastic leukemia oncoprotein 2 (c-erbB-2)] are commonly studied growth factor receptors. There is no ligand for HER2; however, EGFR can be activated by several ligands (Table 2) [32], [33]. The function of individual receptors depends on the biological role of corresponding ligands, which have been shown briefly in the Table 2 [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50]. Nevertheless, ligand-induced EGFR may initiate cellular signaling by promoting a homodimer formation with another receptor molecule (homodimerization) or through transactivation with other family members (heterodimerization) including HER2 [32]. EGFR signaling can involve a number of intracellular molecules such as extracellular signal-regulated kinase (ERK), cyclin D1 and β-catenin [51].
The ErbB family receptors and associated ligands.
| Members | Ligands | Brief description |
|---|---|---|
| EGFR 7p11.2a | Epidermal growth factor (EGF) | It functions as autocrine or paracrine manner and plays a key role in the growth and proliferation of various cells. Dysregulation of the EGF gene has been documented in certain neoplastic growth [34] |
| Transforming growth factor-α (TGF-α) | It is expressed in various cells including macrophages and keratinocytes. Like EGF, the TGF-α gene is involved in several cancers and some cleft lip/palate cases. In addition, TGF-α is associated with Ménétrier disease, a disorder of gastric mucosal hyperplasia [35], [36] | |
| Amphiregulin | Amphiregulin is produced by a number of cells such as epithelial cells, fibroblasts and immune cells. It has been implicated in several biological phenomena, e.g. keratinocyte proliferation, mammary gland development, inflammation and cancer [37] | |
| HB-EGF | Expression of HB-EGF is detected in monocytes/macrophages. HB-EGF plays significant roles in various biological processes, e.g. wound healing, heart development, adipogenesis, atherosclerosis, tumorigenesis. It also acts as the diphtheria toxin receptor [38] | |
| Betacellulin | Betacellulin is expressed by a wide variety of cells. Its biological functions include differentiation of pancreatic β-cells, amelioration of hyperglycemia, promotion of neurogenesis and myelin formation. It is overexpressed in different cancers and associated with prognosis [39], [40] | |
| Epiregulin | Epiregulin takes part in cellular proliferation and angiogenesis, as well as conditions like tissue repair and wound healing. It is also involved in neoplastic process [41], [42] | |
| Epigen | Like EGF, epigen has similar biological actions. It has potent mitogenic effect, though its binding affinity is weaker [43] | |
| HER2 17q12a | ? MUC4 | It is hypothesized that HER2 may form a complex with MUC4, a member of mucin family. Cytokines like IFN-γ and TGF-β also regulate MUC4 expression. An aberrant expression of this glycoprotein has been documented in a number of carcinomas [44] |
| ErbB3 12q13a | Neuregulin (NRG) | The family has four members: NRG1-4 (for ErbB3, NRG1 and 2 are important). NRG1 includes six isoforms: types I–VI. NRG1 plays vital role in the nervous and cardiovascular system development. Moreover, it is involved in different disease conditions such as cancer and schizophrenia [45], [46], [47] |
| Heregulin (HRG) | Structurally similar to NRG, HRG consists of four isoforms: HRG1-4. HRG affects cellular growth, and plays a necessary role in the development and maintenance of the cardiovascular and nervous systems. Abnormal activity of HRG is implicated in various cancers [48], [49], [50] | |
| ErbB4 2q34a | Neuregulin | NRG1-4 (discussed above) |
| Heregulin | HRG1-4 (discussed above) | |
| HB-EGF | – discussed above | |
| Betacellulin | – discussed above | |
| Epiregulin | – discussed above |
aChromosomal location. HB-EGF, heparin-binding EGF-like growth factor; IFN-γ, interferon-γ. HER2 has no known ligand; and ErbB3 has a defective kinase domain. These two receptors act as subunits of the other ErbB family receptors including HER2/ErbB3 heterodimers.
The presence of EGFR is detected in a wide range of cancer types (Table 3 [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77]). Normally, the EGFR gene is located on chromosome 7. However, the EGFR gene could be associated with the extra-chromosomal DNA elements like double minutes (DMs) in neoplastic processes [78]. Nevertheless, the connection between lipids/adiposity and EGFR is complicated. One in vitro study in ECV-304 endothelial cell-line showed that EGFR could be activated by oleic acid (an ω-9 fatty acid) independent of any autocrine secretion of the ligand epidermal growth factor (EGF) or other related mediators [79]. On the other hand, EGF was shown to stimulate proliferation in 3T3-L1 preadipocytes [80]. In addition, using the same 3T3-L1 cells, Pagano et al. [81] demonstrated that EGF can induce the EGFR-HER2 heterodimerization and stimulate receptor tyrosine phosphorylation of both EGFR and HER2. A recent in vivo study (using ApoE−/− and C57BL/6 mice, Table 4 [82], [83], [84], [85], [86], [87], [88], [89]) has recorded the detrimental role of EGFR in the pathogenesis of obesity-related nephropathy [90]. In a clinical study, after analyzing 100 postmenopausal breast cancer specimens, Xuan et al. [91] found that tamoxifen resistance was associated with obesity, and EGFR expression was higher in tamoxifen resistance cases compared to tamoxifen sensitive group (Table 5 [32], [92], [93], [94]). Overall, the status of EGFR in the lipogenic environment is intricate. However, different in vitro and in vivo experiments and studies on human subjects revealed that EGFR could be modulated in the abovementioned circumstances [79], [80], [81], [90], [91].
Findings of selective studies on immunohistochemical expression of EGFR and HER2 in different cancer types or pathologies where obesity is considered as a risk factor.
| Body system | Cancer site | Specimens analyzed | EGFR+ cases, % | HER2+ cases, % | Comments | Investigators |
|---|---|---|---|---|---|---|
| Digestive tract | Esophagogastric (adenocarcinoma) | 220 | 32.7 | 14.1 | EGFR amplification was more common in tumors near gastro-esophageal junction than gastric body | Birkman et al. [52] |
| Esophagogastric (adenocarcinoma) | 52 | 73 | 40 | – | Chan et al. [53] | |
| Esophagogastric (adenocarcinoma) | 293 | 27 | 15 | – | Fuse et al. [54] | |
| Gallbladder | 50 | 74 | 4 | – | Doval et al. [55] | |
| Pancreas | 36 | 50 | 41.7 | EGFR and HER2 were related to clinical stage | Zhang and Yuan [56] | |
| Pancreas | 36 | 50 | 66.7 | EGFR was associated with metastasis | Pryczynicz et al. [57] | |
| Pancreas | 72 | 44 | 1 | – | Walsh et al. [58] | |
| Colon | 127 | 32 | 1 | – | Leung et al. [59] | |
| Colon | 91 | 63 | 2 | – | Takahari et al. [60] | |
| Colon | 86 | 43 | 77 | EGFR was associated with poor prognosis | Khelwatty et al. [61] | |
| Female reproductive organs | Breast (postmenopausal) | 1515 | 13 | 18 | – | Knoop et al. [62] |
| Breast (postmenopausal) | 135 | 49 | 49 | – | Ray et al. [63] | |
| Endometrium | 34 | 23.5 | 88.2 | EGFR was linked with disease progression | Wang et al. [64] | |
| Endometrium | 69 | 49 | 59 | EGFR correlated with metastasis and survival | Khalifa et al. [65] | |
| Endometrium | 63 | 39.7 | 41.3 | HER2 impacted prognosis | Mori et al. [66] | |
| Ovary | 64 | 19 | 11 | – | Goff et al. [67] | |
| Ovary | 123 | 28.5 | 25.2 | – | Ali-Fehmi et al. [68] | |
| Ovary | 783 | 62 | 35 | Depending on tumor grade, HER2+ increased mortality risk | Nielsen et al. [69] | |
| Ovary | 82 | 18.3 | 45.1 | HER2+ had aggressive behavior | Demir et al. [70] | |
| Other cancer typesa | Male breast | 42 | 21 | 16 | – | Ge et al. [71] |
| Male breast | 130 | 12 | 3 | – | Kornegoor et al. [72] | |
| Prostate | 106 | 43 | 24 | Androgen-independent disease | Hernes et al. [73] | |
| Urinary bladder | 67 | 62.7 | 22.4 | – | Kiyoshima et al. [74] | |
| Urinary bladder | 30 | 23 | 60 | – | Naik et al. [51] | |
| Urinary bladder | 45 | 53.3 | 42.2 | – | Enache et al. [75] | |
| Urinary bladder | 72 | 71 | 83 | – | Carlsson et al. [76] |
aLimited or inadequate evidence for the association between obesity and cancer risk [77].
Relevant in vitro and in vivo experimental models in connection with HER2 overexpression.
| In vitro models | In vivo models | |||
|---|---|---|---|---|
| Cancer cell-lines | Normal/ non-tumorigenic cell-lines | |||
| Origin: human | Origin: human | Experimental animals | ||
| Reproductive system | Upper digestive system | Lower digestive system | Mouse models | |
| Breast cancer cells: | Esophageal adenocarcinoma cells: | Colon cancer cells: | Endothelial cells: | ApoE−/− mice |
| BT474 [82], [83] | BIC-1 | Caco-2 [88] | ECV-304 | C57BL/6 mice |
| MCF-7 | FLO | DiFi | MMTV-neu or HER2/neu transgenic mice [89] | |
| MDA-MB-231 | OE19 [85], [86] | DLD-1 | Kidney (embryonic) cells: | MMTV/v-Ha-ras transgenic mice |
| MDA-MB-361 [83] | OE33 [86] | FET | HEK293T | |
| MDA-MB-435s | HCT116 | Rat models | ||
| MDA-MB-453 | Gastric cancer cells: | HT-29 | Mammary epithelial cells: | Sprague-Dawley rats |
| MDA-MB-468 | MKN28 | LoVo | 184.a1 | Wistar rats |
| SK-BR-3 [82], [83] | MKN74 | LS174T [88] | HBL100 | |
| T47D | SW480 | MCF10A (derived from fibrocystic disease) | ||
| Pancreatic cancer cells: | SW613 | |||
| Ovarian cancer cells: | BxPC-3 | Preadipocytes/adipocytes: | ||
| OVCAR-3 | Capan-1 | 3T3-L1 | ||
| SK-OV-3 [84] | CD18/HPAF | |||
| UL-1 | MIA PaCa-2 [87] | Origin: Animals | ||
| Panc-1 | CHO: Chinese hamster ovary cells | |||
| Panc-28 | NMuMG: Mouse mammary epithelial cells | |||
Cell-line/experimental model with reference number(s) indicates higher HER2 expression, although all cells commonly express HER2.
Selective targeted treatment modalities in cancer with reference to EGFR/HER2.
| Therapeutic agents | Pharmacological properties | Targeted cells/biomolecules |
|---|---|---|
| Gefitinib [32], [92] | Tyrosine kinase inhibitor | This drug competes for the tyrosine kinase domain of EGFR and blocks its phosphorylation, which inhibits cellular signal transduction |
| Tamoxifen [93] | Selective estrogen receptor modulator (SERM) | Treatment for hormone-sensitive breast cancer, i.e. tumors that express estrogen receptor (ER). It competes with endogenous estrogens to prevent the activation of ERα |
| Trastuzumab [94] | Monoclonal antibody inhibitor | This agent targets HER2-positive cancer cells (tumors that overexpress HER2 protein). It selectively binds to the extracellular domain of HER2, and can hinder the growth of these cancer cells |
| Ado-trastuzumab emtansine [94] | Antibody-drug conjugate | Monoclonal antibody trastuzumab is linked with a microtubule inhibitor emtansine. After binding of this conjugate with HER2-overexpressing cells and subsequent internalization, emtansine causes cell cycle arrest, apart from trastuzumab-induced inhibition of HER2 signaling pathways |
| Cetuximab [32], [92] | Monoclonal antibody inhibitor | This biologic agent binds to the extracellular domain of EGFR and blocks its signaling system, resulting in cellular growth inhibition and apoptosis |
| Lapatinib [32], [92] | Dual tyrosine kinase inhibitor | This agent is a small molecule tyrosine kinase inhibitor that has been developed to block intracellular signaling pathways of both EGFR and HER2 |
Several studies have observed that leptin can stimulate EGFR signaling. Leptin induced significant tyrosine phosphorylation of EGFR in MKN28 and MKN74 gastric cancer cell-lines [95]. In the same way, it was found that leptin and IGF-1 cotreatment synergistically transactivated EGFR in MDA-MB-468, MDA-MB-231, and MCF-7 breast cancer cells [96]. Alternatively, leptin was shown to stimulate the proliferation of OE33, OE19, BIC-1 and FLO esophageal adenocarcinoma cells via increased gene expression of EGFR-ligands heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor-α (TGF-α) [97]. In an in vivo study (in Wistar rats), administration of leptin increased phosphorylation of EGFR along with c-Src tyrosine kinase and ERK in tissues like aorta and kidney [98]. Furthermore, this experimental hyperleptinemia was accompanied by increased plasma concentration and urinary excretion of lipid peroxidation product isoprostanes. Therefore, it is comprehended that the crosstalk between adipokine leptin and EGFR signaling pathways could alter significantly the behavior of different cell types in both normal and disease conditions (Figure 1).
Interactions among various intracellular signaling molecules, which are connected with EGFR and Ob-R, and their involvement in different cellular events in both normal and pathological conditions.
Characteristics of HER2 expression
Both EGFR and HER2 have been found to be associated with lipid rafts, which are patchy localized regions in the cell membrane and involved in cell signaling. Thus, membrane cholesterol can alter both raft structures and HER2 signaling pathways [99]. Interestingly, it has been suggested that the ErbB proteins including HER2 in the membrane can translocate to the nucleus and regulate a variety of cellular functions, such as cell proliferation, DNA damage repair, and signal transduction, both in normal and cancer cells [100]. In hormone-dependent cells, it is known that estrogen can stimulate the cellular proliferation. Subbaramaiah et al. [101] noticed that overexpression of HER2 was associated with increased activity of aromatase whose one of the predominant locations is in adipose tissue and this enzyme catalyzes the synthesis of estrogens from androgens. Research suggests that HER2 is also connected to other metabolic activities of adipose tissue. For instance, regarding adipogenesis, it has been hypothesized that HER2 might have a role during the differentiation of preadipocytes (3T3-L1) [102]. Adipogenesis is an intricate process of the development of mature adipocytes from precursor cells, and impairment in this process possibly is linked with metabolic pathologies in obesity [103], [104].
Throughout the cardiovascular system, both EGFR and HER2 are abundantly expressed; and hyperleptinemia has been documented to increase HER2 activity in the arterial wall [105]. In contrast, Cha et al. [106] showed that HER2 can induce transcriptional activation of leptin in MCF10A human mammary epithelial cell-line. These two examples indicate a close cooperation between leptin and HER2. Possibly, the interactions between HER2 and leptin are bidirectional involving different intracellular signaling pathways.
Different cardiovascular events like atherosclerosis and its sequelae can be accelerated by conditions such as obesity, type 2 diabetes and metabolic syndrome: these pathologies are frequently associated with abnormal levels of leptin. Interestingly, a study observed a positive association of circulating HER2 with various obesity-related parameters, e.g. hyperglycemia, BMI, triglycerides, and glycated hemoglobin (HbA1c) [107]. Of note, circulating HER2 is derived from the extracellular domain, which can be measured after its release in the blood stream. On the other hand, studies have indicated that obesity might increase the risk of cardiac toxicity in breast cancer patients who received trastuzumab (HER2-targeted monoclonal antibody) therapy [108], [109], [110]. Evidence shows that HER2 plays important physiological roles in the development of the heart and cardiomyocyte survival [111], [112]. Therefore, treatment with trastuzumab could be associated with the deleterious effects of the HER2 blockade (Table 5).
Like the cardioprotective effects of HER2, cardiac development and several survival events in the myocardium are mediated by neuregulin-1 (an EGF-like growth factor, Table 2) [113]. Administration of recombinant human neuregulin-1 in hypercholesterolemic apolipoprotein E-deficient type 1 diabetes mice (ApoE−/− mice, hyperglycemia induced by streptozotocin) has been demonstrated to induce systemic activation of HER2 and ErbB4 receptors in both heart and kidneys [114]. In general, this mouse model is prone to develop disorders such as cardiomyopathy, atherosclerosis, and nephropathy. However, neuregulin-1 treatment prevented left ventricular (LV) dilatation, improved LV contractile function, and reduced atherosclerotic plaque size, along with alleviation of the renal pathologies.
Adipose tissue is the major reservoir for several micronutrients including fat-soluble vitamins such as vitamins A, D and E. These vitamins regulate several genes in adipose tissue and impact strongly the tissue’s biology such as adipogenesis, energy homeostasis, and inflammation [115]. Furthermore, many of these micronutrients have anti-cancer properties [20], [116]. In a study in SK-BR-3 breast cancer cells and HER2/neu transgenic female mice, supplementation of vitamin E isomers tocotrienols reduced both HER2 mRNA and protein in cancer cell-line as well as in tumors [117]. It is worth noting that SK-BR-3 cells are HER2 positive but estrogen receptor negative (ER−) human breast adenocarcinoma cell-line; while HER2/neu or mouse mammary tumor virus (MMTV)-neu transgenic mouse model expresses activated form of the rat homolog of HER2 and develops spontaneous mammary adenocarcinomas.
Like tocotrienols, vitamin D supplementation has also been shown to be associated with significant improvement in prognosis among HER2+ breast cancer patients [118], [119]. Similar results were obtained from studies in MMTV-neu transgenic mice, which were treated with synthetic vitamin D derivatives, characterized by two side-chains attached to carbon-20 (Gemini). Lee et al. [120] observed that the Gemini vitamin D analog (BXL0124) inhibited the growth of HER2-overexpressing mammary tumors through regulating the HER2/AKT/ERK signaling pathways in MMTV-neu transgenic mice. There were more than 50% decrease in tumor growth, tumor weight and tumor multiplicity in the BXL0124 treatment group. Conversely, another study recorded the preventive role of the same analog rather than its therapeutic efficacy [121]. In this study, the BXL0124 treatment only delayed the development of mammary tumors, and decreased the activation of HER2 as well as protein levels of its signaling pathway such as ERK, AKT and cyclin D1. Interestingly, administration of hormonally active vitamin D (calcitriol) has been demonstrated to promote HER2 expression in the myocardium of Sprague-Dawley rats [122]. In addition, the study has documented that calcitriol increased neuregulin-1 protein level. Therefore, accumulating evidence suggests a highly complex role of vitamin D. It is noteworthy that vitamin D regulates several adipose tissue cytokines including leptin [123]. Recent evidence on the association between vitamin D deficiency and obesity clearly indicates that the functions of this vitamin are not limited to the maintenance of bone tissue and calcium metabolism [124], [125], [126], [127], [128].
Overall, HER2 has a number of physiological roles such as regulation of adipogenesis, cardioprotective effect, and participation in vitamin metabolism. Interestingly, several survival pathways in the myocardium are mediated by HER2. In fact, HER2 plays fundamental roles starting from heart development in the embryonic state to maintenance of cardiac function throughout our life. Tumor cells most likely exploit HER2 and associated pathways for their continued survival and cancer progression.
Breast cancer and HER2 in obesity: in vitro and in vivo observations
In an in vitro study, suppression of estrogen receptor beta (ERβ) expression and higher expression of cyclin D1 and anti-apoptotic protein Bcl-2 were documented in HER2+ SK-BR-3 cells and mammary tumor cells from MMTV-neu mice after incubation with serum from obese postmenopausal breast cancer patients [129]. Of note, possibly ERβ expression is correlated with better prognosis. Nevertheless, culture of HER2+ BT474 and SK-BR-3 breast cancer cells in conditioned media from differentiated adipocytes significantly reduced trastuzumab-mediated growth inhibition of HER2+ cells and stimulated rapid phosphorylation of AKT [130].
In a study using BT474 and SK-BR-3 cell-lines, Menendez et al. [131] showed that dietary fatty acids such as α-linolenic acid (ω-3 fatty acid), eicosapentaenoic acid (ω-3), and oleic acid (ω-9) downregulated but linoleic acid (ω-6) increased HER2 extracellular domain concentration. Perhaps, there is a close association between HER2 and fatty acid metabolism. In different HER+ breast and ovarian cancer cell-lines, i.e. in SK-BR-3, BT474, MDA-MB-453, T47D (moderate HER2 expression), MCF-7 (low expression), and SK-OV-3, downregulation of HER2 has been recorded by inhibition of fatty acid synthase (FASN), which catalyzes the formation of long-chain fatty acids [132], [133]. It appears that there is an intimate connection between FASN and HER2, both of which positively regulate each other. Astonishingly, transfection of human mammary epithelial cell-line HBL100 with the FASN gene significantly increased expression levels of EGFR and HER2 proteins [134]. In comparison to HER2(−) breast cancer cells, studies found a metabolically different situation such as lower lipid contents, higher fatty acid saturation, and upregulated FASN in HER2+ breast cancer cells [135], [136]. The investigators used high HER2-expressing BT474 and SK-BR-3 cell-lines, along with MDA-MB-231, MDA-MB-435s and MCF10A cell-lines, which express less to no HER2.
The addition of leptin to HER2+ MDA-MB-361 (ER+) and SK-BR-3 (ER−) breast cancer cell-lines was shown to increase various cellular proteins such as signal transduction molecule PI3K, angiogenic factor VEGF, and cyclooxygenase-2 (COX-2) [14]. Of note, the inducible isoform COX-2 is associated with arachidonic acid metabolism and pro-inflammatory conditions. On the other hand, Soma et al. [137] reported that leptin induced tyrosine phosphorylation of HER2 in SK-BR-3 cells. In addition, Giordano et al. [138] revealed that leptin treatment increased HER2 protein levels in SK-BR-3 cells as well as in stably transfected MCF-7/HER2-18 cells. Conversely, following oncogenic transformation, HER2-transformed mammary epithelial cells were reported to exhibit high mRNA expression of Ob-R and greater response to leptin [139]. In this study, normal human breast epithelium (184.a1 line) and normal mouse mammary epithelial cells (NMuMG) were used. Furthermore, studies found reduced sensitivity to antiestrogen tamoxifen after the administration of leptin to breast cancer cells (MDA-MB-231, MCF-7, and MCF-7/HER2 cell-lines), especially HER2-overexpressing cells [138], [140].
Different breast cancer cells express varied levels of HER2 receptors. A commonly studied HER2+ breast cancer cell-line is SK-BR-3, which exhibited aggressive behavior after incubation with serum from obese postmenopausal breast cancer patients or conditioned media from differentiated adipocytes. In the same way, different dietary fatty acids showed an impact on cellular HER2 levels. A number of studies recorded a close association of HER2 with FASN that catalyzes fatty acid synthesis. Likewise, a relationship was found between HER2 and leptin.
Results of in vivo experiments
In an initial study on diet-induced obesity in MMTV-neu mice, final body weights of obesity-prone mice were heaviest compared to obesity-resistant and low-fat diet control groups; although latency period for cancer development, incidence, metastasis and tumor burden were similar for all groups [141]. However, serum leptin levels were higher in high-fat diet mice group. In a subsequent study, though the time of onset of a first tumor and tumor growth rates were not altered, mice on a high-fat diet had an earlier onset of a second tumor and a twofold greater incidence and a greater absolute number of multiple tumors [142]. Among MMTV-neu mice, a dietary intervention study found that combined intermittent calorie restriction and consumption of eicosapentaenoic acid (ω-3 fatty acid) significantly reduced the mammary tumor incidence (15%) in comparison with ad-libitum control group (87%) [143]. Furthermore, consumption of eicosapentaenoic acid drastically reduced serum leptin levels. Another dietary intervention study on this transgenic mouse model observed that a fatty acid-free diet reduced tumor incidence and delayed tumor appearance but tumor growth rate was unaffected [144]. A recent report has shown that caloric restriction elicited an increase in mammary ERα and ERβ expression in MMTV-neu transgenic mice in comparison with overweight (high-carbohydrate, low-fat diet) and diet-induced obesity (high-carbohydrate, high-fat diet) regimen [145]. In caloric restriction group, both mRNA and protein levels of ERα and ERβ were increased. In addition, mice on the calorie-restricted diet had lower serum levels of leptin, estradiol, insulin and IGF-1.
Apart from the abovementioned MMTV-neu transgenic mice, dietary interventions also have been shown to alter the expression levels of HER2 in other in vivo experimental models. A study of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis in Sprague-Dawley rats reported a decrease of HER2 mRNA and the relevant signal transduction pathway by high-fat olive oil diet in comparison with high-fat corn oil diet [146]. In another study in MMTV/v-Ha-ras transgenic mice, food restriction decreased RNA levels of HER2, along with a reduction in tumor incidence [147]. It is worth mentioning that the transgenic v-Ha-ras mouse model of FVB background expresses the ras oncogene under the control of the MMTV promoter and develops mammary tumors along with neoplastic growth in other sites such as salivary and lymphoid tissues.
Clinical studies on breast cancer and HER2 with reference to obesity
In clinical condition, the association between obesity and HER2-overexpressing breast cancer is perplexing [148], [149], [150]. Nonetheless, Tan et al. [151] recorded that the fat mass and obesity-associated (FTO) gene expression in the HER2-overexpressed subtype of breast cancer was significantly higher. It is noteworthy that the FTO gene is located on chromosome 16, and has a close link with BMI. On the other hand, Bouguerra et al. [152] noticed that obesity was correlated with larger tumors, advanced grade and with ER−, progesterone receptor negative (PR−), and HER2+ breast cancer subtype. Similarly, in a study conducted by Mazzarella et al. [153], obesity significantly correlated with worse overall survival and cumulative incidence of distant metastases in ER−/HER2+ breast cancer.
Considering the clinical usefulness, breast tumors are usually classified according to the immunohistochemical expression of prognostic markers such as ER, PR, and HER2. In general, tumors are categorized into four main molecular subtypes, i.e. luminal A, B, triple negative and HER2-enriched (HER2+, ER− and PR−). However, investigators frequently make additional groupings such as normal-like and luminal B/HER2+ or HER2/luminal-like (HER2+, ER+ and/or PR+). There are also some less commonly used groups, e.g. molecular apocrine, claudin-low and different subtypes of triple negative tumors. Nevertheless, in a recent study, which analyzed 3767 breast cancer patients, it has been observed that overweight premenopausal patients had more HER2-enriched subtype compared to normal weight patients [154]. Furthermore, in postmenopausal patients, HER2/luminal-like subtype was found to be significantly associated with overweight BMI.
In a study conducted in Italy, Capasso et al. [149] evaluated anthropometric and metabolic parameters in order to assess the relationship between the metabolic syndrome and breast cancer. They observed that the waist circumference >88 cm was shown to be significantly associated with HER2+ breast cancer subtype in postmenopausal women. Their study also documented an association between insulin resistance and HER2+ tumors. However, in this study, blood levels of triglycerides and high-density lipoprotein (HDL)-cholesterol were not related to the risk of any molecular subtypes. After analysis of transcriptional biomarkers in blood samples, Alokail et al. [155] found significantly higher HER2 mRNA levels in leukocytes of breast cancer patients compared to lean controls. But, the difference of mRNA levels between overweight/obese and lean controls was not statistically significant. Nonetheless, regarding metabolic syndrome-related parameters, significantly elevated triglycerides and decreased HDL-cholesterol levels were recorded among breast cancer cases than lean controls [155]. Likewise, Jain et al. [156] observed similarly altered levels of relevant blood lipid fractions, though these parameters did not correlate significantly with HER2 expression in breast cancer. On the other hand, a study on lipid metabolism-related proteins/enzymes in metastatic breast cancer revealed an association of HER2 positivity with FASN and acyl-CoA oxidase 1 [157]. The tissue expression of FASN was significantly higher in the HER2 subtype.
In a study on lipid-rich carcinoma of the breast, 71.4% were found to be positive for HER2 expression; whereas only 10.2% were positive for PR and all cases were negative for ER [158]. Over a span of 10 years, the investigators detected 49 patients with lipid-rich carcinoma out of 3206 breast cancer cases. It is worth mentioning that lipid-rich carcinoma is a rare type of breast cancer and characterized by the presence of lipids in the cells. In an interesting study, decreased levels of lipid peroxidation product malondialdehyde (MDA) and increased levels of antioxidant enzyme superoxide dismutase (SOD) were found in the HER+ group of breast cancer [159]. Overexpression of HER2 might be beneficial for cancer cells to protect against lipid peroxidation and their survival.
Tumors of other organs and HER2 expression
Malignant diseases of the digestive system
A study demonstrated that two principal lysophospholipids, lysophosphatidic acid and sphingosine 1-phosphate, induced phosphorylation of HER2 in two human gastric cancer cell-lines, well-differentiated MKN28 adenocarcinoma cells and moderately differentiated MKN74 tubular adenocarcinoma cells [160]. It is noteworthy that lysophosphatidic acid and sphingosine 1-phosphate are biologically active lipid mediators that are involved in a wide range of functions such as cellular proliferation, cell motility and angiogenesis. On the other hand, after analyzing 110 gastric cancer specimens along with 96 specimens of normal gastric mucosa, Geng et al. [161] found significantly higher expression levels of leptin, Ob-Rb and HER2 in gastric cancer tissues compared to normal mucosa. Moreover, there was a correlation between the expression of leptin and HER2; both were significantly associated with the depth of tumor invasion, lymph node involvement, VEGF expression and the American Joint Committee on Cancer (AJCC) staging (a modified TNM classification system).
In the gastrointestinal (GI) tract, both stomach and colorectal cancers are the common malignancies and the leading causes of mortality worldwide. Li et al. [162] recorded elevated expression levels of HER2 and FASN in Caco-2 cells, a human colon adenocarcinoma cell-line that exhibits characteristics of enterocytic differentiation. In addition, they observed that expression of FASN and intracellular signal transduction molecules PI3K and AKT were downregulated when HER2 was silenced. This phenomenon was associated with decreased proliferation and increased apoptosis of cells. Vadlamudi et al. [163] examined the expression and activation of the EGFR family members in a number of human colorectal carcinoma cell-lines, e.g. DiFi, LS174T, Caco-2, SW480, HT-29, SW613, HCT116 and FET. They demonstrated that HER2 and ErbB3 (or HER3) formed heterodimeric complexes and phosphorylated tyrosine residues in colorectal cancer cells. It is considered that dimerization between HER2 (an orphan receptor) and ErbB3 (a kinase-defective protein) occurs frequently (Figure 2); and this heterodimer can activate PI3K, a lipid kinase involved in the proliferation, survival, adhesion and motility of tumor cells [164]. Furthermore, Vadlamudi et al. [163] reported that the HER2/ErbB3 signaling induced the expression of COX-2 and accumulation of prostaglandin E2 (PGE2) through the arachidonic acid pathway. PGE2 is a known pro-inflammatory lipid mediator and promotes tumor progression via several mechanisms such as regulation of cell proliferation, induction of tumor cells to secrete growth factors, and immunomodulation for the escape of tumor cells from effective immunosurveillance [165].
Members of the ErbB receptor family and an outline of their dimer formation.
Zhao et al. [166] examined different human colon cancer cell-lines, e.g. HCT116, LoVo, HT-29, SW480, DLD-1 and Caco-2; and found that HER2 was overexpressed in these cells. In addition, they described that HER2 can activate signaling pathways including ERK1/2, STAT3, mechanistic target of rapamycin (mTOR) and AKT, which play important roles in cell proliferation and survival. These signaling molecules are also activated in HER2-overexpressing tumors from other parts of the digestive system. For instance, a recent study investigated the role of hyperinsulinemia in Barrett’s esophagus, dysplasia and esophageal adenocarcinoma [167]. The state of insulin resistance correlated with HER2 expression and downstream mediators AKT and mTOR in esophageal tissue. Furthermore, experiments on different pancreatic cancer cell-lines (e.g. BxPC-3, Capan-1, CD18/HPAF, MIA PaCa-2, Panc-1 and Panc-28) exemplified the downstream pathways of HER2 in detail [168], [169].
Tumors of the genitourinary/excretory organs
In an interesting report, HER2 status was evaluated in different cancer types [170]. The authors recorded frequencies of 51%, 44%, 26% and 25% in Wilm’s tumor (pediatric kidney cancer), cancer of the urinary bladder, pancreatic cancer and breast carcinoma, respectively. Other tumors tested had frequencies below 20% [170]. It is noteworthy that HER2 expression has been reported in various pediatric cancers including Wilm’s tumor; however, in comparison with adult cancers, several features of HER2 such as expression pattern and clinical outcome perhaps are different in pediatric cancers [171]. Fascinatingly, there are many similarities in the risk factors of pancreatic and urinary bladder cancers such as tobacco use and obesity-related conditions like diabetes and metabolic syndrome [172], [173], [174], [175], [176].
A study in three ovarian cancer cell-lines, i.e. SK-OV-3, OVCAR-3 and UL-1 cells, recorded the expression of HER2 gene product in these cell-lines [177]. In addition, HER2 gene product was enhanced by treatment with lipids derived from the ascitic fluid of ovarian cancer patients. In another study, using Chinese hamster ovary (CHO) cells and HEK293T human embryonic kidney cells, Eisenberg et al. [178] observed that upon leptin binding both short and long isoforms of Ob-R phosphorylated and thereby activated HER2, which enhanced MAPK activity. This phenomenon was independent of the involvement of EGFR family ligands.
A study that analyzed 100 specimens of NSCLC revealed significantly higher expression of leptin (71%), Ob-Rb (62%) and HER2 (53%) in tumors than in normal lung tissue [179]. Of note, the majority of lung cancers are NSCLC, which includes predominant squamous cell carcinomas and adenocarcinomas. Nevertheless, it is worth mentioning that there are certain interesting similarities between leptin and EGFR/HER2 signaling pathways (Figure 1). For instance, intracellular signaling molecules such as PI3K, AKT and ERK can participate in both pathways, and they are associated with cell proliferation and survival. Therefore, synergistic effects of these two pathways could alter significantly the behavior of tumors.
Malignancies of the GI tract are a major cancer burden worldwide. Obesity is a risk factor for different GI tract cancers. A growing body of evidence suggests that among tumors of the GI tract, HER2 is associated with several obesity-related/tumor progression phenomena such as expression of leptin, FASN and COX-2. Different lipogenic pathways are also influenced by HER2. On the other hand, obesity and/or obesity-related pathologies have been linked with a number of other malignancies such as tumors of the ovary and urologic cancers. Studies documented an interaction between leptin and HER2 in ovarian cells.
Conclusion
Perhaps, HER2 is closely associated with a wide range of biomolecules of lipid metabolism, e.g. peroxisome proliferator-activated receptor gamma (PPARγ), mTOR, lipin-1 (phosphatidate phosphatase) and triglycerides [180]. All of these components play important roles in obesity. For instance, the mTOR is a PI3K-like protein kinase and actively participates in lipid metabolism, adipogenesis and insulin/IGF-1 growth factor signaling. It is noteworthy that insulin resistance and aberrant IGF-1 signaling pathways are potential mechanisms that link obesity to the development of cancer. Interestingly, both HER2 and IGF signaling systems utilize certain common intracellular molecules such as PI3K, AKT and MAPK, which are frequently activated in neoplastic growth where they induce cellular proliferation.
Postmenopausal breast cancer is the best example of obesity-related tumor development. It is worth noting that the majority of breast cancer occurs in postmenopausal women, and HER2 is overexpressed in approximately 20%–30% of breast malignancies [181], [182], [183]. Moreover, irrespective of menopausal status, overweight and obesity are associated with an elevated risk of inflammatory breast cancer, which constitutes around 5% of all breast cancer cases [184], [185]. Regarding obesity-related breast tumor development, few pathological events are commonly considered such as abnormal bioavailable estrogen, IGF-1, and pro-inflammatory cytokines or adipokines [181]. Excess adipose tissue is responsible for increased biosynthesis of estrogen (through the aromatization of androgens) and pro-inflammatory adipokines like leptin. Fascinatingly, leptin also activates several intracellular signaling molecules that are connected with the downstream signaling pathways of HER2 and IGF-1.
Like the functions of VEGF in the cardiovascular system and neoplastic growth, HER2 possibly plays similar contrasting roles. Evidence suggests beneficial effects of HER2 in cardiomyocytes. Although HER2-targeted therapy like trastuzumab shows encouraging results, more insight is needed into the precise functions of HER2 in our physiological system. A better understanding is helpful in the development of new anti-HER2 therapeutic approaches.
Acknowledgments
The author is thankful to Dr. Irv Freeman, Vice President, LECOM at Seton Hill, for his support.
Author Statement
Research funding: Authors state no funding involved.
Conflict of interest: Authors state no conflict of interest.
Informed consent: Informed consent is not applicable.
Ethical approval: The conducted research is not related to either human or animals use.
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Articles in the same Issue
- Review Articles
- Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment
- The functional significance of 14-3-3 proteins in cancer: focus on lung cancer
- Original Articles
- The effect of thyroid dysfunction on nesfatin-1 and adiponectin levels in rats
- Back pain in pregnancy among office workers: risk factors and its impact on quality of life
- Do exercises improve back pain in pregnancy?
- Case Report
- Ectopic adrenal tissue associated with borderline mucinous cystadenoma of ovary: a case report with review of the literature
Articles in the same Issue
- Review Articles
- Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment
- The functional significance of 14-3-3 proteins in cancer: focus on lung cancer
- Original Articles
- The effect of thyroid dysfunction on nesfatin-1 and adiponectin levels in rats
- Back pain in pregnancy among office workers: risk factors and its impact on quality of life
- Do exercises improve back pain in pregnancy?
- Case Report
- Ectopic adrenal tissue associated with borderline mucinous cystadenoma of ovary: a case report with review of the literature
