Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: ERBB2
Cytogenetic location: 17q12 Genomic coordinates (GRCh38): 17:39,688,094-39,728,658 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q12 | ?Visceral neuropathy, familial, 2, autosomal recessive | 619465 | Autosomal recessive | 3 |
| Adenocarcinoma of lung, somatic | 211980 | 3 | ||
| Gastric cancer, somatic | 613659 | 3 | ||
| Glioblastoma, somatic | 137800 | 3 | ||
| Ovarian cancer, somatic | 167000 | 3 |
The oncogene originally called NEU was derived from rat neuro/glioblastoma cell lines (Yang-Feng et al., 1985). It encodes a tumor antigen, p185, which is serologically related to EGFR, the epidermal growth factor receptor (131550).
Coussens et al. (1985) identified a potential cell surface receptor of the tyrosine kinase gene family and characterized it by cloning the gene. Its primary sequence is very similar to that of the human epidermal growth factor receptor. Because of the seemingly close relationship to the human EGF receptor, the authors called the gene HER2.
Semba et al. (1985) identified an ERBB-related gene, ERBB2, that is distinct from the ERBB gene (131550), called ERBB1 by these authors.
Di Fiore et al. (1987) indicated that NEU and HER2 are both the same as ERBB2.
Akiyama et al. (1986) raised antibodies against a synthetic peptide corresponding to 14 amino acid residues at the COOH terminus of a protein deduced from the ERBB2 nucleotide sequence. With these antibodies, they precipitated the ERBB2 gene product from adenocarcinoma cells and demonstrated it to be a 185-kD glycoprotein with tyrosine kinase activity.
Semba et al. (1985) observed about 30-fold amplification of ERBB2 in a human adenocarcinoma of the salivary gland.
Fukushige et al. (1986) observed amplification and elevated expression of the ERBB2 gene in a gastric cancer cell line.
Di Fiore et al. (1987) demonstrated that overexpression alone can convert the gene for a normal growth factor receptor, namely, ERBB2, into an oncogene.
Van de Vijver et al. (1988) found a correlation between overexpression of NEU protein and the large-cell, comedo growth type of ductal carcinoma. They could find no correlation, however, with lymph node status or tumor recurrence.
Slamon et al. (1989) described the role of HER2/NEU in breast (114480) and ovarian cancer (167000), which together account for one-third of all cancers in women and approximately one-quarter of cancer-related deaths in females.
Interleukin-6 (IL6; 147620) is a cytokine that was initially recognized as a regulator of immune and inflammatory responses, but also regulates the growth of many tumor cells, including prostate cancer. Overexpression of ERBB2 and ERBB3 (190151) has been implicated in the neoplastic transformation of prostate cancer. Qiu et al. (1998) showed that treatment of a prostate cancer cell line with IL6 induced tyrosine phosphorylation of ERBB2 and ERBB3, but not ERBB1/EGFR (131550). They also showed the ERBB2 forms a complex with the gp130 subunit of the IL6 receptor (IL6R; 147880) in an IL6-dependent manner. This association was important because the inhibition of ERBB2 activity resulted in abrogation of IL6-induced MAPK activation. Thus, ERBB2 is a critical component of IL6 signaling through the MAP kinase pathway. These findings showed how a cytokine receptor can diversify its signaling pathways by engaging with a growth factor receptor kinase.
Overexpression of ERBB2 confers Taxol resistance in breast cancers. Yu et al. (1998) found that overexpression of ERBB2 inhibits Taxol-induced apoptosis. Taxol activates CDC2 kinase (116940) in MDA-MB-435 breast cancer cells, leading to cell cycle arrest at the G2/M phase and, subsequently, apoptosis. A chemical inhibitor of CDC2 and a dominant-negative mutant of CDC2 blocked Taxol-induced apoptosis in these cells. Overexpression of ERBB2 in MDA-MB-435 cells by transfection transcriptionally upregulates CDKN1A (116899) which associates with CDC2, inhibits Taxol-mediated CDC2 activation, delays cell entrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. In CDKN1A antisense-transfected MDA-MB-435 cells or in p21-/- MEF cells, ERBB2 was unable to inhibit Taxol-induced apoptosis. Therefore, CDKN1A participates in the regulation of a G2/M checkpoint that contributes to resistance to Taxol-induced apoptosis in ERBB2-overexpressing breast cancer cells.
ERBB2 overexpression confers resistance to taxol-induced apoptosis by inhibiting p34(CDC2) activation. One mechanism is via ERBB2-mediated upregulation of p21(CIP1), or CDKN1A, which inhibits CDC2. Tan et al. (2002) reported that the inhibitory phosphorylation on tyr15 (Y15) of CDC2 was elevated in ERBB2-overexpressing breast cancer cells and primary tumors. ERBB2 bound to and colocalized with cyclin B (123836)-CDC2 complexes and phosphorylated CDC2 Y15. The ERBB2 kinase domain was sufficient to directly phosphorylate CDC2 Y15. Increased CDC2 with phosphorylated Y15 in ERBB2-overexpressing cells corresponded with delayed M phase entry. Expression of a nonphosphorylatable mutant of CDC2 rendered cells more sensitive to taxol-induced apoptosis. Thus, the authors concluded that ERBB2 can confer resistance to taxol-induced apoptosis by directly phosphorylating CDC2.
Doherty et al. (1999) described a secreted protein of approximately 68 kD, designated herstatin, as the product of an alternative ERBB2 transcript that retains intron 8. This alternative transcript specifies 340 residues identical to subdomains I and II from the extracellular domain of p185ERBB2, followed by a unique C-terminal sequence of 79 amino acids encoded by intron 8. The recombinant product of the alternative transcript specifically bound to ERBB2-transfected cells and was chemically crosslinked to p185ERBB2, whereas the intron-encoded sequence alone also bound with high affinity to transfected cells and associated with p185 solubilized from cell extracts. The herstatin mRNA was expressed in normal human fetal kidney and liver, but was at reduced levels relative to p185ERBB2 mRNA in carcinoma cells that contained an amplified ERBB2 gene. Herstatin appears to be an inhibitor of p185ERBB2, because it disrupts dimers, reduces tyrosine phosphorylation of p185, and inhibits the anchorage-independent growth of transformed cells that overexpress ERBB2.
Pegram et al. (1997) and Mehta et al. (1998) presented evidence indicating that HER2 may be involved in determining the chemosensitivity of human cancers, especially breast and ovarian cancer. It has also been implicated in the development of resistance to the antiestrogen tamoxifen in both advanced disease and in an adjuvant setting (De Placido et al., 1998). Trastuzumab (Herceptin) is a humanized monoclonal antibody that appears to block growth signals transmitted by HER2 to the nucleus and enhances response to chemotherapeutic agents (Pietras et al., 1998; Slamon et al., 2001).
The HER2 gene is amplified and HER2 is overexpressed in 25 to 30% of breast cancers, increasing the aggressiveness of the tumor. Slamon et al. (2001) found that herceptin increased the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2. In a review, Roses (2004) pointed to ERBB2 and herceptin for breast cancer as a prime example of the usefulness of pharmacogenetics in drug development.
Vermeer et al. (2003) showed that in differentiated human airway epithelia, heregulin-alpha (142445) is present exclusively in the apical membrane and the overlying airway surface liquid, physically separated from ERBB2, ERBB3 (190151), and ERBB4 (600543), which segregate to the basolateral membrane. This physical arrangement creates a ligand-receptor pair poised for activation whenever epithelial integrity is disrupted. Indeed, immediately following a mechanical injury, heregulin-alpha activates ERBB2 in cells at the edge of the wound, and this process hastens restoration of epithelial integrity. Likewise, when epithelial cells are not separated into apical and basolateral membranes (polarized), or when tight junctions between adjacent cells are opened, heregulin-alpha activates its receptor. This mechanism of ligand-receptor segregation on either side of epithelial tight junctions may be vital for rapid restoration of integrity following injury, and hence critical for survival. This model also suggested a mechanism for abnormal receptor activation in diseases with increased epithelial permeability.
Certain malignant breast tumors (see 114480) are characterized by a high prediction uncertainty ('low-confidence') with respect to ESR1 (133430) status. Kun et al. (2003) analyzed these 'low-confidence' tumors and determined that their 'uncertain' prediction status arose as a result of widespread perturbations in multiple genes whose expression is important for ESR1 subtype discrimination. Patients with 'low-confidence' ESR-positive tumors exhibited a significantly worse overall survival (p = 0.03) and shorter time to distant metastasis (p = 0.004) compared with their 'high-confidence' ESR-positive counterparts. Elevated expression of ERBB2 was significantly correlated with a breast tumor exhibiting a 'low-confidence' prediction. Although ERBB2 signaling has been proposed to inhibit the transcriptional activity of ESR1, a large proportion of the perturbed genes in the 'low-confidence'/ERBB2-positive samples are not known to be estrogen responsive. Kun et al. (2003) proposed that a significant portion of the effects of ERBB2 on ESR-positive breast tumors may involve ESR-independent mechanisms of gene activation, which may contribute to the clinically aggressive behavior of the 'low-confidence' breast tumor subtype.
The biosynthetic enzyme fatty acid synthase (FASN; 600212) is the major enzyme required for the anabolic conversion of dietary carbohydrates to fatty acids, and it functions normally in cells with high lipid metabolism. Under normal physiologic conditions, any FASN increase is tightly regulated by a number of environmental, hormonal, and nutritional signals. However, infiltrating carcinomas of the breast constitutively express high levels of FASN compared to nontransformed human epithelial tissues. Overexpression and hyperactivity of FASN is associated with more aggressive breast and ovarian cancers. The early and nearly universal upregulation of FASN in many human cancers and its association with poor clinical outcome strengthened the hypothesis that FASN is involved in development, maintenance, and enhancement of the malignant phenotype. Menendez et al. (2004) identified a molecular link between FASN and the HER2 oncogene, a marker for poor prognosis that is overexpressed in 30% of breast and ovarian cancers. Pharmacologic FASN inhibitors were found to suppress p185(HER2) oncoprotein expression and tyrosine kinase activity in breast and ovarian cancers overexpressing HER2. Similar suppression was observed when FASN gene expression was silenced by using the highly sequence-specific mechanism of RNA interference (RNAi).
Kawasaki and Taira (2004) presented evidence that vector-based small interfering RNAs (siRNAs) targeted to the ERBB2 promoter induced DNA methylation and transcriptional silencing in human cells. A retraction was published.
Jones et al. (2006) used microarrays comprising virtually every Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domain encoded in the human genome to measure the equilibrium dissociation constant of each domain for 61 peptides representing physiologic sites of tyrosine phosphorylation on the 4 ErbB receptors. By slicing through the network at different affinity thresholds, Jones et al. (2006) found surprising differences between the receptors. Most notably, EGFR (131550) and ErbB2 became markedly more promiscuous as the threshold was lowered, whereas ErbB3 did not. Because EGFR and ErbB2 are overexpressed in many human cancers, Jones et al. (2006) concluded that the extent to which promiscuity changes with protein concentration may contribute to the oncogenic potential of receptor tyrosine kinases.
Child et al. (1999) found that the 5-prime UTR of HER2 mRNA contains a short upstream ORF encoding a 6-amino acid peptide that repressed translation of the downstream coding region. In HER2-overexpressing breast cancer cells, Mehta et al. (2006) found that the 3-prime UTR of HER2 mRNA could override translational inhibition mediated by the HER2 upstream ORF. Within the 3-prime UTR, Mehta et al. (2006) identified a translational derepression element that bound several proteins involved in RNA management, including HuR (ELAVL1; 603466), and hnRNP C1/C2 (HNRNPC; 164020), and hnRNP A1 (HNRNPA1; 164017).
Schwann cells are thought to be the primary host cells for Mycobacterium leprae, and demyelination is a common pathologic feature in leprosy (see 246300) and other neurodegenerative diseases. Using immunoblot and immunofluorescence analyses, Tapinos et al. (2006) observed marked, early phosphorylation of ERK1 (MAPK1; 176948)/ERK2 (MAPK3; 601795) accompanied by demyelination in the absence of apoptosis after exposure of rat and human Schwann cell cultures to M. leprae. The M. leprae-induced ERK1/ERK2 activation was mediated by binding of M. leprae to the extracellular domain of ERBB2, leading to its phosphorylation without ERBB3 heterodimerization. Tapinos et al. (2006) concluded that M. leprae binds ERBB2 directly and induces excessive ERK1/ERK2 signaling, which subsequently causes demyelination. They proposed that ERBB2 or other receptor tyrosine kinases may serve as key sites for initiating demyelination.
In whole mouse heart and brain lysates, Negro et al. (2006) found that Erbb2 interacted with beta-2 adrenergic receptor (ADRB2; 109690), which is a G protein-coupled receptor (GPCR). Erbb2 was transactivated by Ucn2 (605902) in cardiac myocytes. Coexpression of Erbb2 with GPCRs in COS-7 cells resulted in ligand-dependent complex formation and Mapk (see MAPK1; 176948) activation.
Hurtado et al. (2008) showed that estrogen-estrogen receptor (ESR; see 133430) and tamoxifen-ESR complexes directly repress ERBB2 transcription by means of a cis-regulatory element within the ERBB2 gene in human cell lines. Hurtado et al. (2008) implicated the paired box-2 gene product (PAX2; 167409) in a previously unrecognized role, as a crucial mediator of ESR repression of ERBB2 by the anticancer drug tamoxifen. Hurtado et al. (2008) showed that PAX2 and the ESR coactivator AIB1/SRC3 (601937) compete for binding and regulation of ERBB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ERBB2 by ESR-PAX2 links these 2 breast cancer subtypes and suggests that aggressive ERBB2-positive tumors can originate from ESR-positive luminal tumors by circumventing this repressive mechanism. Hurtado et al. (2008) concluded that their data provided mechanistic insight into the molecular basis of endocrine resistance in breast cancer.
Godinho et al. (2014) used a 3-dimensional model system and other approaches to culture human mammary epithelial cells, and found that centrosome amplification triggers cell invasion. This invasive behavior is similar to that induced by overexpression of the breast cancer oncogene ERBB2 and indeed enhances invasiveness triggered by ERBB2. These data indicated that, through increased centrosomal microtubule nucleation, centrosome amplification increases RAC1 (602048) activity, which disrupts normal cell-cell adhesion and promotes invasion. Godinho et al. (2014) concluded that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation.
Jordan et al. (2016) analyzed circulating tumor cells from 19 women with ER+/HER2- primary tumors, 84% of whom had acquired circulating tumor cells expressing HER2. Cultured circulating tumor cells maintain discrete HER2+ and HER2- subpopulations: HER2+ circulating tumor cells are more proliferative but not addicted to HER2, consistent with activation of multiple signaling pathways; HER2- circulating tumor cells show activation of Notch (190198) and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2+ and HER2- circulating tumor cells interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within 4 cell doublings. Although HER2+ and HER2- circulating tumor cells have comparable tumor-initiating potential, differential proliferation favors the HER2+ state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2- phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic circulating tumor cell-derived tumor models. Jordan et al. (2016) concluded that their results pointed to distinct yet interconverting phenotypes within patient-derived circulating tumor cells, contributing to progression of breast cancer and acquisition of drug resistance.
Crystal Structure
Cho et al. (2003) reported the crystal structures of the entire extracellular regions of rat HER2 at a 2.4-angstrom resolution and human HER2 complexed with the trastuzumab antigen-binding fragment (Fab) at 2.5 angstroms. These structures revealed a fixed conformation for HER2 that resembles a ligand-activated state, and showed HER2 poised to interact with other ErbB receptors in the absence of direct ligand binding. Trastuzumab binds to the juxtamembrane region of HER2, identifying this site as a target for anticancer therapies.
Bostrom et al. (2009) described an antibody with an antigen-binding site that binds 2 distinct proteins with high affinity. They isolated a variant of Herceptin, a therapeutic monoclonal antibody that binds human HER2, on the basis of its ability to simultaneously interact with vascular endothelial growth factor (VEGF; 192240). Crystallographic and mutagenesis studies revealed that distinct amino acids of this antibody, called bH1, engage HER2 and VEGF energetically, but there is extensive overlap between the antibody surface areas contacting the 2 antigens. An affinity-improved version of bH1 inhibited both HER2- and VEGF-mediated cell proliferation in vitro and tumor progression in mouse models. The authors argued that such 'two-in-one' antibodies challenge the monoclonal antibody paradigm of 1 binding site, 1 antigen.
Although ERBB2 is unique among the 4 human ERBB receptors, Alvarado et al. (2009) demonstrated that it is the closest structural relative of the single EGF receptor (see 131550) family member in Drosophila. Genetic and biochemical data showed that Drosophila Egfr is tightly regulated by growth factor ligands, yet a crystal structure showed that it, too, lacks the intramolecular tether seen in human EGFR, ErbB3 (190151), and ErbB4 (600543). Instead, a distinct set of autoinhibitory interdomain interactions hold unliganded Drosophila Egfr in an inactive state. All of these interactions are maintained, and even extended, in ErbB2, arguing against the suggestion that ErbB2 lacks autoinhibition. Alvarado et al. (2009) therefore suggested that normal and pathogenic ErbB2 signaling may be regulated by ligands in the same way as Drosophila Egfr.
Yang-Feng et al. (1985) found that the human NEU homolog, which they designated NGL (to avoid confusion with neuraminidase, which is also symbolized NEU), maps to 17q12-q22 by in situ hybridization and to 17q21-qter in somatic cell hybrids. Thus, the smallest region of overlap (SRO) is 17q21-q22.
Coussens et al. (1985) assigned the HER2 gene to 17q21-q22 by Southern blot analysis of somatic cell hybrid DNA and by in situ hybridization. This chromosomal location of the gene is coincident with that of the NEU oncogene, which suggested that the 2 genes may in fact be the same; indeed, sequencing indicated that they are identical (Francke, 1988).
By chromosome sorting combined with velocity sedimentation and Southern hybridization, Fukushige et al. (1986) assigned the ERBB2 gene to chromosome 17. By hybridization to sorted chromosomes and to metaphase spreads with a genomic probe, Fukushige et al. (1986) mapped the ERBB2 locus to 17q21. This is the chromosome 17 breakpoint in acute promyelocytic leukemia (APL).
Kaneko et al. (1987) used a cDNA probe for ERBB2 and by in situ hybridization to APL cells with a 15;17 chromosome translocation located the gene to the proximal side of the breakpoint. They suggested that both the gene and the breakpoint are located in band 17q21.1 and, further, that the ERBB2 gene is involved in the development of leukemia.
Popescu et al. (1989) localized ERBB2 to 17q11-q21 by in situ hybridization. By in situ hybridization to chromosomes derived from fibroblasts carrying a constitutional translocation between 15 and 17, Popescu et al. (1989) showed that the ERBB2 gene was relocated to the derivative chromosome 15; the gene could thus be localized to 17q12-q21.32.
By family linkage studies using multiple DNA markers in the 17q12-q21 region, Anderson et al. (1993) placed the ERBB2 gene on the genetic map of the region.
By fluorescence in situ hybridization, Muleris et al. (1997) mapped the ERBB2 gene to 17q21.1.
Associations with Cancer
In a population-based case-control study of the val655-to-ile polymorphism (164870.0001), Xie et al. (2000) found that the val allele was associated with an increased risk of breast cancer, particularly among younger women. Because of the significant ethnic differences in the incidence of breast cancer and other solid tumors, Ameyaw et al. (2002) undertook a study of 7 ethnic groups from 3 separate continents. The frequency of the val allele was highly variable between populations (1 to 24%). The continental African populations had a lower frequency than did the other subjects, corresponding with the lower incidence and lower risk of breast cancer in African women compared with Caucasian and African American women.
The Cancer Genome Project and Collaborative Group (2004) sequenced the ERBB2 gene from 120 primary lung tumors (see 211980) and identified 4% that had mutations within the kinase domain; in the adenocarcinoma subtype of lung cancer, 10% of cases had mutations. In-frame deletions within the kinase domain of EGFR (e.g., 131550.0001) are associated with lung tumors that respond to therapy with gefitinib, an EGFR inhibitor. The Cancer Genome Project and Collaborative Group (2004) suggested that ERBB2 inhibitors, which had to that time proved to be ineffective in treating lung cancer, should be clinically reevaluated in the specific subset of patients with lung cancer whose tumors carry ERBB2 mutations.
The Cancer Genome Atlas Research Network (2008) reported the interim integrative analysis of DNA copy number, gene expression, and DNA methylation aberrations in 206 glioblastomas and nucleotide sequence alterations in 91 of the 206 glioblastomas. The authors also observed that the RTK/RAS/PI3K signaling pathway was altered in 88% of glioblastomas. EGFR mutation or amplification was present in 45% and ERBB2 mutation was reported in 8%. In an erratum, the group stated that the somatic mutations reported in ERBB2 were actually an artifact of DNA amplification and were not validated in unamplified DNA.
Familial Visceral Neuropathy 2, Autosomal Recessive
In a Turkish sister and brother with visceral neuropathy (VSCN2; 619465), Le et al. (2021) identified homozygosity for a missense mutation in the ERBB2 gene (A710V; 164870.0009), for which their consanguineous parents were heterozygous. Functional analysis of the mutant protein demonstrated loss of function.
Lin et al. (2000) noted that Erbb2 is activated by neuregulin (see NRG1; 142445) and is expressed in Schwann and muscle cells in the developing neuromuscular junction. Using Erbb2-deficient mice, they showed that Erbb2 is essential for in vivo development of the neuromuscular junction.
Morris et al. (1999) genetically rescued the cardiac defect of Erbb2 null mouse embryos, which otherwise died at embryonic day 11. The rescued embryos died at birth and displayed a severe loss of both motor and sensory neurons. Motor and sensory axons were defasciculated and aberrantly projected within their final target tissues. Schwann cell precursors were present within the dorsal root ganglion and proliferated normally, but their ability to migrate was decreased. Schwann cells were completely absent in the peripheral nerves. Acetylcholine receptors clustered within the central band of the mutant diaphragm muscle; however, the clusters were dispersed and morphologically different from those in control muscle.
Andrechek et al. (2002) developed a muscle-specific Erbb2 null mouse model. Mice were viable and showed progressive defects in proprioception due to loss of muscle spindles. The authors found that even a partial reduction in Erbb2 levels reduced the number of muscle spindles. Histologic analysis of the muscle revealed an otherwise normal architecture. Induction of muscle injury, however, revealed a defect in muscle regeneration. Primary myoblasts lacking Erbb2 exhibited extensive apoptosis upon differentiation into myofibers.
Chan et al. (2002) found that homozygous mice expressing a kinase-dead Erbb2 cDNA under the transcriptional control of the endogenous promoter died at midgestation and displayed the same spectrum of embryonic defects seen in Erbb2 knockout mutants. They concluded that the catalytic activity of Erbb2 is essential for normal embryonic development.
Dankort et al. (2001) studied female transgenic mice expressing mutant Erbb2 lacking all known tyrosine phosphorylation sites and mice expressing mutant Erbb2 lacking all tyrosine phosphorylation sites except those for either Grb2 (108355) or Shc (600560) adaptor molecules. In contrast to mice expressing the phosphorylation-deficient Erbb2, which developed focal mammary tumors after a long latency period with low penetrance, mice expressing Erbb2 coupled with Grb2 or Shc rapidly developed mammary tumors. Mice with Erbb2 coupled with Grb2 also developed lung metastases at substantially higher rates than mice with Erbb2 coupled with Shc.
An activated mutant form of ERBB2 is rarely found in human cancer. Instead, wildtype ERBB2 is overexpressed and/or amplified in 10 to 30% of breast cancers, where it correlates with chemoresistance and poor patient prognosis. Trastuzumab, a monoclonal antibody against ERBB2, is an effective treatment for a subset of patients with advanced breast cancer. Liu et al. (2002) used a transgenic mouse model with targeted aberrant overexpression of ERBB2 to determine whether genetic instability is associated with mammary tumorigenesis in vivo in the absence of heritable defects in known DNA maintenance genes. They found that this gene, which is not thought to be involved in repair of DNA damage or maintenance of its integrity, affects the occurrence of mutations. Furthermore, the type of mutations recovered in the mammary tumor tissues when ERBB2 was overexpressed bore no resemblance to those found when mismatch repair was altered. Whereas transversion mutations are relatively rare events in spontaneous background mutation and are not elevated in mismatch repair-deficient cells, the tumors in ErbB2 mice had a 6- to 7-fold increase in transversions, mainly GC to TA, whereas transitions were increased less than 2-fold, and frameshifts were not affected (see commentary by de Boer, 2002).
Amplification of the gene encoding the ERBB2 receptor tyrosine kinase is critical for the progression of several forms of breast cancer. In a large-scale clinical trial, treatment with trastuzumab (Herceptin), a humanized blocking antibody against ERBB2, led to marked improvement in survival (Slamon et al., 2001). However, cardiomyopathy was uncovered as an adverse side effect, suggesting an important role of ERBB2 signaling as a modifier of heart failure. To investigate the physiologic role of ERBB2 signaling in the adult heart, Crone et al. (2002) generated mice with deletion of Erbb2 restricted to the cardiac ventricles. These Erbb2-deficient conditional mutant mice were viable and displayed no overt phenotype. However, physiologic analysis revealed the onset of multiple independent parameters of dilated cardiomyopathy, including chamber dilation, wall thinning, and decreased contractility. Additionally, cardiomyocytes isolated from these conditional mutants were more susceptible to anthracycline toxicity. Erbb2 signaling in cardiomyocytes is therefore essential for the prevention of dilated cardiomyopathy.
Cardiomyopathies develop in a proportion of breast cancer patients treated with herceptin, and the incidence of such complications is increased by combination with standard chemotherapy. Gene knockout studies have demonstrated that the ERBB2 receptor, together with its coreceptor ERBB4 (600543) and the ligand NRG1, are essential for normal development of the heart ventricle. Ozcelik et al. (2002) used Cre-loxP technology to mutate ErbB2 specifically in the ventricular cardiomyocytes of mice. Conditional mutant mice developed a severe dilated cardiomyopathy, with signs of cardiac dysfunction generally appearing by the second postnatal month. Ozcelik et al. (2002) inferred that signaling from the ErbB2 receptor, which is enriched in T-tubules in cardiomyocytes, is crucial for adult heart function.
Crone et al. (2003) created conditional mutant mice with loss of Erbb2 expression targeted to the enteric nervous system. Conditional mutants exhibited retarded growth, distended colons, and premature death, resembling Hirschsprung disease (142623). Enteric neurons and glia were present at birth in the colons of mutant mice, but there was marked loss of multiple classes of enteric neurons and glia by 3 weeks of age.
In order to study the role of Erbb2 in breast tissue development, Jackson-Fisher et al. (2004) transplanted embryonic mouse Erbb2 -/- mammary buds into cleared mammary fat pads of immature wildtype female mice. The mutant mammary buds supported outgrowth of an epithelial tree, but they showed a delay in ductal penetration. The growth defect was associated with structural defects in terminal end buds, characterized by a decrease in body cell number, increased presence of cap-like cells in the preluminal compartment, and large luminal spaces.
Escher et al. (2005) demonstrated that neuromuscular junctions (NMJs) can form in the absence of the neuregulin receptors ErbB2 and ErbB4 (600543) in mouse muscle. Postsynaptic differentiation was, however, induced by agrin (103320). Escher et al. (2005) therefore concluded that neuregulin signaling to muscle is not required for NMJ formation. The effects of neuregulin signaling to muscle may be mediated indirectly through Schwann cells.
Negro et al. (2006) found that Mapk activation and cardiac contractility were markedly impaired in Erbb2-null mouse hearts infused with Ucn2, an agonist of G protein-coupled receptors (GPCRs). The authors concluded that ERBB2 is a coreceptor for GPCR signaling in the heart.
Guo et al. (2006) found that deletion of the signaling domain of beta-4 integrin (ITGB4; 147557) suppressed tumor onset and invasive growth in a mouse model of Erbb2-induced mammary carcinoma. Ex vivo studies showed that beta-4 formed a complex with Erbb2 and enhanced activation of Stat3 (102582) and Jun (165160). Stat3 contributed to disruption of epithelial adhesion and polarity, whereas Jun was required for hyperproliferation. Deletion of the beta-4 signaling domain enhanced the efficacy of Erbb2-targeted therapy. Guo et al. (2006) concluded that beta-4 integrin promotes tumor progression by amplifying ERBB2 signaling and is a potential target for breast cancer therapy.
The sequences of human ERBB2 cDNA clones reported by Yamamoto et al. (1986) and Coussens et al. (1985) differed at codon 655, which encoded isoleucine or valine, respectively. Papewalis et al. (1991) and Ehsani et al. (1993) described a G-to-A polymorphism in codon 655 responsible for this variation between GTC and ATC. See 164870.0002.
Ehsani et al. (1993) described a G-to-A polymorphism at codon 654 of the ERBB2 gene resulting in a variation from valine to isoleucine. The ile-ile and ile-val configurations of codons 654 and 655 had frequencies of 0.782 and 0.206, respectively; these were designated B1 and B2 in accordance with Genome Data Base nomenclature. A rare B3 allele, val-val, had a frequency of 0.012. Among 680 chromosomes analyzed, the val-ile combination was not found, suggesting that it is very rare.
In a nonsmall cell lung cancer (adenocarcinoma) (211980), the Cancer Genome Project and Collaborative Group (2004) identified an insertion/duplication of GCATACGTGATG at nucleotide 2322 of the ERBB2 gene, resulting in a 4-amino acid insertion (AYVM) at codon 774. This mutation was not identified in DNA from normal tissue. The same insertion was found in tumor tissue only from another individual, and also in tumor tissue from a third individual from whom no normal tissue was available for comparison.
In a nonsmall cell lung cancer (adenocarcinoma) (211980), the Cancer Genome Project and Collaborative Group (2004) identified an insertion of CTGTGGGCT at nucleotide 2335 of the ERBB2 gene, resulting in a 3-amino acid insertion (VGS) starting at codon 779.
In a nonsmall cell lung cancer (adenocarcinoma) (211980), the Cancer Genome Project and Collaborative Group (2004) identified a 2-bp substitution in the ERBB2 gene, TT-CC at nucleotides 2263 and 2264, resulting in a leu755-to-pro (L755P) substitution.
In a glioblastoma (137800), the Cancer Genome Project and Collaborative Group (2004) identified a 2740G-A transition in the ERBB2 gene that caused a glu914-to-lys substitution (E914K).
In a gastric tumor (137215), the Cancer Genome Project and Collaborative Group (2004) identified a somatic 2326G-A transition in the ERBB2 gene that caused a gly776-to-ser (G776S) substitution.
In an ovarian tumor (167000), the Cancer Genome Project and Collaborative Group (2004) identified a somatic 2570A-G transition in the ERBB2 gene that caused an asn857-to-ser (N857S) substitution.
In a Turkish sister and brother (family 5) with visceral neuropathy (VSCN2; 619465), Le et al. (2021) identified homozygosity for a c.2129C-T transition (c.2129C-T, NM_004448.3) in the ERBB2 gene, resulting in an ala710-to-val (A710V) substitution at a highly conserved residue within the kinase domain. Their consanguineous parents were heterozygous for the mutation, which was not found in the gnomAD database. Western blot analysis of Neuro-2a transfected cells transfected with the mutant protein revealed a drastic decrease in phosphorylation of both ERBB2 and ERBB3 (190151) compared to wildtype.
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