ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))
2011-05-01 Luca Braccioli , Marilena V Iorio , Patrizia Casalini AffiliationIdentity
HGNC
LOCATION
17q12
IMAGE
LEGEND
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
LOCUSID
ALIAS
CD340,HER-2,HER-2/neu,HER2,MLN
FUSION GENES
DNA/RNA
Description
Sequence length: 40522; CDS: 3678. 30 exons, 26 coding exons; total exon length: 4816, max exon length: 969, min exon length: 48. Number of SNPs: 17.
Polymorphisms: allelic variations at amino acid positions 654 and 655 of isoform (a) (positions 624 and 625 of isoform (b)) have been reported, with the most common allele B1 (Ile-654/Ile-655); allele B2 (Ile-654/Val-655); allele B3 (Val-654/Val-655). This nucleotide polymorphism could be associated with development of gastric carcinoma and with breast cancer risk, particularly among younger women.
Polymorphisms: allelic variations at amino acid positions 654 and 655 of isoform (a) (positions 624 and 625 of isoform (b)) have been reported, with the most common allele B1 (Ile-654/Ile-655); allele B2 (Ile-654/Val-655); allele B3 (Val-654/Val-655). This nucleotide polymorphism could be associated with development of gastric carcinoma and with breast cancer risk, particularly among younger women.
Transcription
Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized.
- mRNA transcript variant: this variant (1) represents the shorter transcript but encodes the longer isoform (a) (protein: erbB-2 isoform (a)).
- mRNA transcript variant: this variant (2) (protein: erbB-2 isoform (b)) contains additional exons at its 5 end and lacks an alternate 5 noncoding exon, compared to variant (1). These differences result in translation initiation at an in-frame, downstream AUG and an isoform (b) with a shorter N-terminus compared to isoform (a).
- mRNA transcript variant: herstatin HER2-ECD 1300 bp alternative erbB-2 transcript that retains intron 8. This alternative transcript specifies 340 residues identical to subdomains I and II from the extracellular domain of p185erbB-2 followed by a unique C-terminal sequence of 79 aa encoded by intron 8. The herstatin mRNA is expressed in normal human fetal kidney and liver, but is at reduced levels relative to p185erbB-2 mRNA in carcinoma cells that contain an amplified erbB-2 gene.
- mRNA transcript variant: an alternative transcript form of the human homologous gene erbB-2, containing an in-frame deletion encompassing exon 19, has been detected in human breast carcinomas.
- mRNA transcript variant: an alternative transcript form of the human homologous gene erbB-2, called HER2Δ16, has been detected in human breast carcinomas. This splicing variant, contains an in-frame deletion and encodes a receptor lacking exon 16, which immediately precedes the transmembrane domain containing two cysteines. The loss of these cysteine residues might induce a change in the conformation of HER2 receptor extracellular domain that promotes intermolecular disulfide bonding and, in turn, homodimers capable of transforming cells. Ectopic expression of HER2Δ16 promotes receptor dimerization, cell invasion, and trastuzumab resistant tumor cell lines. The potential metastatic and oncogenic properties of HER2Δ16 were mediated through direct coupling of HER2Δ16 to Src kinase.
- mRNA transcript variant: this variant (1) represents the shorter transcript but encodes the longer isoform (a) (protein: erbB-2 isoform (a)).
- mRNA transcript variant: this variant (2) (protein: erbB-2 isoform (b)) contains additional exons at its 5 end and lacks an alternate 5 noncoding exon, compared to variant (1). These differences result in translation initiation at an in-frame, downstream AUG and an isoform (b) with a shorter N-terminus compared to isoform (a).
- mRNA transcript variant: herstatin HER2-ECD 1300 bp alternative erbB-2 transcript that retains intron 8. This alternative transcript specifies 340 residues identical to subdomains I and II from the extracellular domain of p185erbB-2 followed by a unique C-terminal sequence of 79 aa encoded by intron 8. The herstatin mRNA is expressed in normal human fetal kidney and liver, but is at reduced levels relative to p185erbB-2 mRNA in carcinoma cells that contain an amplified erbB-2 gene.
- mRNA transcript variant: an alternative transcript form of the human homologous gene erbB-2, containing an in-frame deletion encompassing exon 19, has been detected in human breast carcinomas.
- mRNA transcript variant: an alternative transcript form of the human homologous gene erbB-2, called HER2Δ16, has been detected in human breast carcinomas. This splicing variant, contains an in-frame deletion and encodes a receptor lacking exon 16, which immediately precedes the transmembrane domain containing two cysteines. The loss of these cysteine residues might induce a change in the conformation of HER2 receptor extracellular domain that promotes intermolecular disulfide bonding and, in turn, homodimers capable of transforming cells. Ectopic expression of HER2Δ16 promotes receptor dimerization, cell invasion, and trastuzumab resistant tumor cell lines. The potential metastatic and oncogenic properties of HER2Δ16 were mediated through direct coupling of HER2Δ16 to Src kinase.
Proteins
HER2 protein: schematic representation. Receptor tyrosin-kinases (RTKs) are cell surface allosteric enzymes consisting of: an extracellular ligand-binding domain (blue); a single transmembrane (TM) domain has an extensive homology to the epidermal grow factor receptor (brown); a cytoplasmic domain with catalityc activity (green).
Description
erbB2 encodes a 185-kDa, 1255 amino acids, orphan receptor tyrosine kinase, and displays potent oncogenic activity when overexpressed. The proto-oncogene consists of three domains: a single transmembrane domain that separates an intracellular kinase domain from an extracellular ligand-binding domain. An aberrant form of HER2, missing the extracellular domain, so-called HER2p95, has been found in some breast cancers. HER2p95 is constitutively active because the external domain of these receptors acts as an inhibitor until they are bound by ligand. This isoform can cause resistance to trastuzumab, an antibody that works by binding to a domain in the external domain of HER2. HER2p95 fragments arise through at least 2 different mechanisms: proteolytic shedding of the extracellular domain of the full-length receptor and translation of the mRNA encoding HER2 from internal initiation codons. Shedding of the ectodomain of HER2 generates a 95- to 100-kDa HER2 p95 membrane-anchored fragment. Translation of the mRNA encoding HER2 can be initiated from the AUG codon that gives rise to the full-length protein of 1255 amino acids or, alternatively, from 2 internal initiation codons at positions 611 and 678, located upstream and downstream of the transmembrane domain, respectively.
Expression
HER2 protein is expressed in several human organs and tissues: normal epithelium, endometrium and ovarian epithelium and at neuromuscular level; prostate, pancreas, lung, kidney, liver, heart, hematopoietic cells. HER2 expression is low in mononuclear cells from bone marrow, peripheral blood (PB) and mobilized PB. The higher expression has been found in cord blood-derived cells. Quiescent CD34+ progenitor cells from all blood sources and resting lymphocytes are HER2 negative, but the expression of this receptor is up-regulated during cell-cycle recruitment of progenitor cells. Similarly, it increases in mature, hematopoietic proliferating cells, underlying the correlation between HER2 and the proliferating status of hematopoietic cells.
Localisation
Plasma membrane.
Function
Activation and interactions
For the other member of the HER family, ligand binding induces receptor homo- or heterodimerization, which is essential for TKs activation and subsequent recruitment of target proteins, in turn initiating a complex signaling cascade that leads into distinct transcriptional programs. There are several HER-specific ligands. HER2, which apparently has no direct or specific ligand, plays a major coordinating role in the HER network because of its ability to enhance and stabilize the dimerization: each receptor with a specific ligand appears in fact to prefer HER-2 as its heterodimeric partner. HER-2-containing heterodimers are characterized by extremely high signaling potency because HER-2 dramatically reduces the rate of ligand dissociation, allowing strong and prolonged activation of downstream signaling pathways.
For the other member of the HER family, ligand binding induces receptor homo- or heterodimerization, which is essential for TKs activation and subsequent recruitment of target proteins, in turn initiating a complex signaling cascade that leads into distinct transcriptional programs. There are several HER-specific ligands. HER2, which apparently has no direct or specific ligand, plays a major coordinating role in the HER network because of its ability to enhance and stabilize the dimerization: each receptor with a specific ligand appears in fact to prefer HER-2 as its heterodimeric partner. HER-2-containing heterodimers are characterized by extremely high signaling potency because HER-2 dramatically reduces the rate of ligand dissociation, allowing strong and prolonged activation of downstream signaling pathways.
Signaling and cellular
The most important intracellular pathways activated by HER2 are those involving mitogen activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K). HER2 expression in cancer, besides its role in proliferation, enhances and prolongs survivals signals, associating up-regulation of this receptor to the malignant phenotype. At the same time, and depending on cellular status, the role of this receptor in controlling cell fate can also lead to differentiation and apoptosis.
Physiological
Role in development and differentiation:
- HER2 has several non-oncogenic roles in regulating growth, differentiation, apoptosis and/or remodeling in normal mammary glands. Dominant-negative forms of HER2 have significant defects in mammary development and lactation.
- HER2 has an important role in development and function of heart. Cre-Lox technology to mutate erbB-2 specifically in ventricular cardiomyocytes leads to a severe cardiomyopathy. This is inferred also by the adverse cardiac side effects observed in breast cancer patients treated with the monoclonal anti-HER2 Ab Trastuzumab.
- HER2 has a role in control of Schwann cell myelination and it has been demonstrated that HER2 signaling is also critical for oligodendrocyte differentiation in vivo.
- HER2 has a dual role in both muscle spindle maintenance and survival of myoblasts. Muscle-specific HER2 KO results in fact in viable mice with a progressive defect in proprioception due to loss of muscles spindles.
Homology
Homolog to avian erythroblastic leukemia viral (v-erb-b) oncogen 2.
Mutations
Somatic
The Cancer Genome Project and Collaborative Group sequenced the erbB-2 gene from 120 primary lung tumors and identified 4% that had mutations within the kinase domain; in the adenocarcinoma subtype of lung cancer, 10% of cases had mutations.
In non small cell lung cancer (adenocarcinoma) the following erbB-2 mutations were found: insertion/duplication of GCATACGTGATG at nucleotide 2322 of the erbB-2 gene, resulting in a 4-amino acid insertion (AYVM) at codon 774. Insertion of CTGTGGGCT at nucleotide 2335 of the erbB-2 gene, resulting in a 3-amino acid insertion (VGS) starting at codon 779; a 2-bp substitution in the erbB-2 gene, TT-CC at nucleotides 2263 and 2264, resulting in a leu755-to-pro (L755P) substitution.
In lung cancer a C44645G transition in the erbB-2 gene that caused a pro1170-to-ala substitution (P1170A).
In a glioblastoma a 2740G-A transition in the erbB-2 gene that caused a glu914-to-lys substitution (E914K).
In a gastric tumor a 2326G-A transition in the erbB-2 gene that caused a gly776-to-ser (G776S) substitution.
In an ovarian tumor, a 2570A-G transition in the erbB-2 gene that caused an asn857-to-ser (N857S) substitution.
In non small cell lung cancer (adenocarcinoma) the following erbB-2 mutations were found: insertion/duplication of GCATACGTGATG at nucleotide 2322 of the erbB-2 gene, resulting in a 4-amino acid insertion (AYVM) at codon 774. Insertion of CTGTGGGCT at nucleotide 2335 of the erbB-2 gene, resulting in a 3-amino acid insertion (VGS) starting at codon 779; a 2-bp substitution in the erbB-2 gene, TT-CC at nucleotides 2263 and 2264, resulting in a leu755-to-pro (L755P) substitution.
In lung cancer a C44645G transition in the erbB-2 gene that caused a pro1170-to-ala substitution (P1170A).
In a glioblastoma a 2740G-A transition in the erbB-2 gene that caused a glu914-to-lys substitution (E914K).
In a gastric tumor a 2326G-A transition in the erbB-2 gene that caused a gly776-to-ser (G776S) substitution.
In an ovarian tumor, a 2570A-G transition in the erbB-2 gene that caused an asn857-to-ser (N857S) substitution.
Implicated in
Entity name
Hematological malignancies
Disease
HER2 expression can be detected in blast cells from patients with hematological malignancies including acute lymphoblastic leukemia (ALL). It could be used as a potential target for the application of HER2-directed treatment strategies in ALL including vaccination approaches.
Entity name
Bladder cancer
Prognosis
HER2 is overexpressed in 25% to 40% of several human tumors and associated with the malignancy of the disease, high mitotic index and a shorter survival time for the patient. Overexpression of ErbB-2 is also associated with transitional cell carcinoma of the bladder. HER2 overexpression occurs in muscle-invasive urothelial carcinomas of the bladder and is associated with worse survival; amplifications of erbB-2 gene are also frequently linked to alterations of the TOP2A gene in bladder cancer. Furthermore, HER2 overexpression and amplification in urothelial carcinoma of the bladder is found associated with MYC co-amplification.
Entity name
Breast carcinoma
Prognosis
Normal tissues have a low content of HER2 membrane protein. Overexpression of HER2 is seen in 20% of breast and it confers worse biological behavior and clinical aggressiveness in breast cancer. Breast cancers can have up to 25 to 50 copies of the HER2 gene and up to a 40- to 100-fold increase in HER2 protein resulting in 2 million receptors expressed at the tumor cell surface. The differential HER2 expression between normal tissues and tumors helps to define HER2 as an ideal treatment target. Trastuzumab, the first treatment targeting HER2, is well tolerated in patients and has little toxicity because its effects are relatively specific for cancer cells overexpressing HER2. HER2 amplification is a relatively early event in human breast tumorigenesis, occurring in almost 50% of in situ carcinomas. HER2 status is maintained during progression to invasive disease and to nodal and distant metastasis. The fact that only 20% of invasive breast cancers are HER2 amplified suggests that many HER2-amplified in situ cancers never progress to the invasive stage. HER2 amplification defines a subtype of breast cancer with a unique signature of genes and this is maintained during progression. Some tumors lose HER2 expression following treatment with trastuzumab, presumably by selection of a HER2-negative clone not killed by treatment. Conversely, HER2 may become positive in some initially negative tumors over time, especially after endocrine therapy targeting ER. Indeed, estrogen receptor has been shown to downregulate HER2 and, conversely, HER2 is able to downregulate ER expression. Therefore, it is not surprising that blocking ER might upregulate HER2 and that blocking HER2 might upregulate ER. HER2-amplified breast cancers have unique biological and clinical characteristics. They have increased sensitivity to certain cytotoxic agents such as doxorubicin, relative resistance to hormonal agents, and propensity to metastasize to the brain and viscera. HER2-amplified tumors have an increased sensitivity to doxorubicin possibly due to coamplification of the topoisomerase-2 gene, which is near the HER2 locus on chromosome 17 and is the target of the drug. Half of HER2-positive breast cancers are ER positive but they generally have lower ER levels, and many have p53 alterations. These tumors have higher proliferation rates and more aneuploidy and are associated with poorer patient prognosis. The poor outcome is dramatically improved with appropriate chemotherapy combined with the HER2-targeting drug trastuzumab. Overexpression of the erbB-2 gene is associated with tumor aggressiveness, and with patient responsiveness to doxorubicin, cyclophosphamide, methotrexate, fluorouracil (CMF), and to paclitaxel, whereas tamoxifen was found to be ineffective and even detrimental in patients with HER2-positive tumors. In Pagets disease of breast, HER2 protein overexpression is caused by amplification of the erbB-2 gene. HER2 has a role in this disease of the breast, where the epidermis of the nipple is infiltrated by large neoplastic cells of glandular origin. It seems that binding of heregulin-alpha to the receptor complex on Paget cells results in chemotaxis of these breast cancer cells. The isoforms HER2p95 and HER2Δ16 are found in some breast cancers and the expression of these hyperactive forms of HER2 may contribute to the malignant progression.
Entity name
Cervical cancer
Prognosis
HER2 may be activated in the early stage of pathogenesis of cervical carcinoma in geriatric patients and is frequently amplified in squamous cell carcinoma of the uterine cervix.
Entity name
Childhood medulloblastoma
Prognosis
Overexpression of HER2 in medulloblastoma is associated with poor prognosis and metastasis and HER2-HER4 receptor heterodimerization is of particular biological significance in this disease.
Entity name
Colorectal cancer
Prognosis
Overexpression of HER2 occurs in a significant number of colorectal cancers. It was significantly associated with poor survival and related to tumor progression in colorectal cancer.
Entity name
Oral squamous cell carcinoma
Prognosis
E6/E7 proteins of HPV type 16 and HER2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells. Overexpression of HER2 receptor is a frequent event in oral squamous cell carcinoma and is correlated with poor survival.
Entity name
Gastric cancer
Prognosis
HER2 amplification/overexpression does not seem to play a role in the molecular pathogenesis of most gastrinomas. However, mild gene amplification occurs in a subset of them, and overexpression of this receptor is associated with aggressiveness of the disease. HER2 overexpression in patients with gastric cancer, and it has been solidly correlated to poor outcomes and a more aggressive disease. The overall HER2 positive rate is about 22%. HER2 overexpression rate in gastric cancer varies according to the site of the tumor. A higher overexpression rate (36%) was shown in gastroesophageal junction (GEJ) tumors in comparison to 21% in gastric tumors.
Entity name
Germ-cell testicular tumor
Prognosis
A significant correlation was observed between HER2 overexpression and clinical outcome in germ-cell testicular tumors.
Entity name
Cholangiocarcinoma
Prognosis
Data are still controversial about HER2 role in this carcinoma. Increased HER2 expression contributes to the development of cholangiocarcinogenesis into an advanced stage associated with tumor metastasis. In addition, overexpression of HER2 and COX-2 correlated directly with tumor differentiation. However, other studies report that HER2 expression is associated with more favorable clinical features, such as a polypoid macroscopic type and absence of other organ involvement, and has been reported that the proportion of HER2-positive cases in papillary adenocarcinoma is higher than in other histological types and is associated with an early disease stage. HER2 is preferentially expressed in well differentiated component, and it is also expressed in dedifferentiated components in progressive cases.
Entity name
Lung cancer
Prognosis
HER2 is overexpressed in less than 20% of patients with non-small cell lung cancer (NSCLC) and studies have shown that overexpression of this receptor is correlated with a poor prognosis in both resected and advanced NSCLC. HER2 overexpression has an important function in the biology of NSCLC and may have a prognostic value for patients with metastatic NSCLC.
Entity name
Prognosis
Higher frequency of HER2 expression has been observed in samples from patients with metastatic disease at presentation and at the time of relapse, and it correlates with worse histologic response and decreased event-free survival. HER2 could be an effective target for the immunotherapy of osteosarcoma, especially the type with high metastatic potential.
Entity name
Ovarian cancer
Prognosis
HER2 overexpression varies from 9% to 32% of all cases of ovarian cancer and its overexpression is more frequent in advanced stage of ovarian cancer. Overexpression of HER2 in ovarian cancer cells leads to faster cell growth, higher abilities in DNA repair and colony formation. A cross-talk between HER2 and estrogen receptor (ER) was identified in ovarian cancer cells. Estrogen has been proven to induce the phosphorylation of HER2, and initiate the HER2s signaling pathway.
Entity name
Pancreatic adenocarcinoma
Prognosis
Overexpression of HER-2 in pancreatic adenocarcinoma seems to be a result of increased transcription rather than gene amplification. The coexpression of HER2 oncogene protein, epidermal growth factor receptor, and TGF-beta1 in pancreatic ductal adenocarcinoma is related to the histopathological grades and clinical stages of tumors. The blockade of HER2 inhibits the growth of pancreatic cancer cells in vitro. HER2 overexpression was reported to accumulate in well differentiated pancreas adenocarcinomas whereas it is only infrequently found in poorly differentiated or undifferentiated tumors, in vivo and in vitro analyses have suggested that targeting HER2 might increase treatment effects of conventional chemotherapies of pancreas adenocarcinoma. However, unlike in breast cancer, the application of antibodies directed against HER2 has not yet become an established therapy for pancreas adenocarcinoma.
Entity name
Prostate cancer
Prognosis
HER2 plays pivotal roles in prostate cancer. Studies have shown that 25% of untreated primary tumors, 59% of localized tumors after neoadjuvant hormone therapy, and 78% of metastatic tumors overexpressed HER2. Several lines of evidence have implicated HER2 as a key mediator in the recurrence of prostate cancer to a hormone-refractory, androgen-independent tumor, which is the hallmark of prostate cancer progress. The driving force for prostate cancer recurrence is the reactivation of androgen receptor (AR), which is a type of nuclear receptors, activated by steroid hormone but ablated in hormonal therapy. Phosphorylation and reactivation of AR stimulate cancer cell growth and trigger tumor progression. It has been observed that overexpression of HER2 kinase enhanced AR function and hormone-independent growth in prostate tumor cells. HER2 activated AR through the MAPK pathway. Additionally, the HER2/HER3 dimmer increases AR protein stability and promotes the binding of AR to the promoter region of its target genes, resulting in AR activation in an androgen-depleted environment.
Entity name
Salivary gland tumor
Prognosis
Several results demonstrated significant positive staining of HER2 in the salivary tumorigenic tissue but not in the surrounding non-tumorigenic tissue, pointing to a biological role in the tumorigenic process. HER2 amplification is present predominantly in tumors with high HER2 expression and seems to be the dominant mechanism for HER2 overexpression in this tumor type.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 11895493 | 2002 | c-erbB-2 and c-Met expression relates to cholangiocarcinogenesis and progression of intrahepatic cholangiocarcinoma. | Aishima SI et al |
| 14724563 | 2004 | E6/E7 proteins of HPV type 16 and ErbB-2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells. | Al Moustafa AE et al |
| 12052879 | 2002 | ErbB2 is required for muscle spindle and myoblast cell survival. | Andrechek ER et al |
| 21343397 | 2011 | p95HER2 and breast cancer. | Arribas J et al |
| 10550311 | 1999 | Fluctuation of HER2 expression in breast carcinomas during the menstrual cycle. | Balsari A et al |
| 8524214 | 1995 | Neu differentiation factor activation of ErbB-3 and ErbB-4 is cell specific and displays a differential requirement for ErbB-2. | Beerli RR et al |
| 14696181 | 2004 | Solution structure of ADO1, a toxin extracted from the saliva of the assassin bug, Agriosphodrus dohrni. | Bernard C et al |
| 7544646 | 1995 | The receptor tyrosine kinase p185HER2 is expressed on a subset of B-lymphoid blasts from patients with acute lymphoblastic leukemia and chronic myelogenous leukemia. | Bühring HJ et al |
| 14679128 | 2004 | HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group. | Camilleri-Broët S et al |
| 8874330 | 1996 | c-erb B2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases. | Carlomagno C et al |
| 15254961 | 2004 | Role of HER receptors family in development and differentiation. | Casalini P et al |
| 16601290 | 2006 | Role of exon-16-deleted HER2 in breast carcinomas. | Castiglioni F et al |
| 15139049 | 2004 | beta-Catenin and p53 analyses of a breast carcinoma tissue microarray. | Chung GG et al |
| 10629373 | 2000 | Overexpression of p53 and HER-2/neu and c-myc in primary fallopian tube carcinoma. | Chung TK et al |
| 15120910 | 2004 | Genetic and pathologic significance of 1p, 17p, and 18q aneusomy and the ERBB2 gene in colorectal cancer and related normal colonic mucosa. | Cianciulli A et al |
| 12910292 | 2003 | Immunohistological study of NM 23 and C-erbB-2 expression in primary tumor and metastases of colorectal adenocarcinoma. | Delektorskaya VV et al |
| 2181668 | 1990 | EGF receptor and erbB-2 tyrosine kinase domains confer cell specificity for mitogenic signaling. | Di Fiore PP et al |
| 10485918 | 1999 | The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor. | Doherty JK et al |
| 12143054 | 2002 | ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions. | Endo K et al |
| 14719098 | 2004 | The expression and prognostic significance of HER-2 in colorectal cancer and its relationship with clinicopathological parameters. | Essapen S et al |
| 12209684 | 2002 | Does HER2/neu expression provide prognostic information in patients with advanced urothelial carcinoma? | Gandour-Edwards R et al |
| 10704452 | 2000 | A dual role of erbB2 in myelination and in expansion of the schwann cell precursor pool. | Garratt AN et al |
| 9696035 | 1998 | Increased expression of c-erbB-2 in hormone-dependent breast cancer cells inhibits cell growth and induces differentiation. | Giani C et al |
| 9242460 | 1997 | Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. | Gilbertson RJ et al |
| 12097278 | 2002 | Her-2/neu expression and gene amplification in gastrinomas: correlations with tumor biology, growth, and aggressiveness. | Goebel SU et al |
| 9130710 | 1997 | ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. | Graus-Porta D et al |
| 18441328 | 2008 | HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. | Gravalos C et al |
| 21204711 | 2011 | HER2: biology, detection, and clinical implications. | Gutierrez C et al |
| 18628098 | 2008 | HER2 overexpression and amplification in urothelial carcinoma of the bladder is associated with MYC coamplification in a subset of cases. | Hansel DE et al |
| 15190415 | 2004 | Amplification and overexpression of HER-2/neu in invasive ductal carcinomas of the pancreas and pancreatic intraepithelial neoplasms and the relationship to the expression of p21(WAF1/CIP1). | Hermanová M et al |
| 20836684 | 2010 | Biological considerations and clinical applications of new HER2-targeted agents. | Higa GM et al |
| 14981584 | 2004 | The role of HER2/neu expression and trastuzumab in non-small cell lung cancer. | Hirsch FR et al |
| 19680294 | 2009 | Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer. | Hirsch FR et al |
| 7592681 | 1995 | Binding of Neu differentiation factor with the extracellular domain of Her2 and Her3. | Horan T et al |
| 12451999 | 2002 | [Expression and clinical significance of p53 and c-erbB2 in geriatric women with cervical carcinoma]. | Huang YW et al |
| 15026342 | 2004 | Cell surface expression of epidermal growth factor receptor and Her-2 with nuclear expression of Her-4 in primary osteosarcoma. | Hughes DP et al |
| 19055823 | 2008 | The genetic polymorphisms of HER-2 and the risk of lung cancer in a Korean population. | Jo UH et al |
| 14614020 | 2003 | Identification of patients with transitional cell carcinoma of the bladder overexpressing ErbB2, ErbB3, or specific ErbB4 isoforms: real-time reverse transcription-PCR analysis in estimation of ErbB receptor status from cancer patients. | Junttila TT et al |
| 11839675 | 2002 | Characterization of the HER-2/neu oncogene by immunohistochemical and fluorescence in situ hybridization analysis in oral and oropharyngeal squamous cell carcinoma. | Khan AJ et al |
| 12843257 | 2003 | The role of ErbB2 signaling in the onset of terminal differentiation of oligodendrocytes in vivo. | Kim JY et al |
| 11751494 | 2001 | HER-2/neu overexpression as a poor prognostic factor for patients with metastatic breast cancer undergoing high-dose chemotherapy with autologous stem cell transplantation. | Kim YS et al |
| 20103665 | 2010 | Radiosensitization of epidermal growth factor receptor/HER2-positive pancreatic cancer is mediated by inhibition of Akt independent of ras mutational status. | Kimple RJ et al |
| 12198768 | 2002 | Overexpression of c-erbB-2 protein correlates with chromosomal gain at the c-erbB-2 locus and patient survival in advanced colorectal carcinomas. | Knösel T et al |
| 7954254 | 1994 | Long-term follow-up study of patients with gastric adenomas with malignant transformation. An immunohistochemical and histochemical analysis. | Kolodziejczyk P et al |
| 15292386 | 2004 | Her-2/neu gene amplification and response to paclitaxel in patients with metastatic breast cancer. | Konecny GE et al |
| 14520697 | 2003 | A single nucleotide polymorphism in the transmembrane domain coding region of HER-2 is associated with development and malignant phenotype of gastric cancer. | Kuraoka K et al |
| 9808159 | 1998 | A novel splice variant of HER2 with increased transformation activity. | Kwong KY et al |
| 14751135 | 2004 | ERBB2 amplification is superior to protein expression status in predicting patient outcome in serous ovarian carcinoma. | Lassus H et al |
| 14520464 | 2003 | HER2/neu overexpression in the development of muscle-invasive transitional cell carcinoma of the bladder. | Latif Z et al |
| 7477377 | 1995 | Requirement for neuregulin receptor erbB2 in neural and cardiac development. | Lee KF et al |
| 15330164 | 2004 | Clinical relevance of HER-2/neu expression in germ-cell testicular tumors. | Mándoky L et al |
| 11839672 | 2002 | HER-2-positive breast carcinomas as a particular subset with peculiar clinical behaviors. | Ménard S et al |
| 10481944 | 1999 | Pathobiologic identification of two distinct breast carcinoma subsets with diverging clinical behaviors. | Ménard S et al |
| 11208823 | 2001 | Response to cyclophosphamide, methotrexate, and fluorouracil in lymph node-positive breast cancer according to HER2 overexpression and other tumor biologic variables. | Ménard S et al |
| 7905784 | 1994 | ERBB2 (HER2/neu) oncogene is frequently amplified in squamous cell carcinoma of the uterine cervix. | Mitra AB et al |
| 19671734 | 2009 | An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance. | Mitra D et al |
| 12560435 | 2003 | HER2 overexpression and doxorubicin in adjuvant chemotherapy for resectable breast cancer. | Moliterni A et al |
| 7907434 | 1994 | erbB-2 expression in well-differentiated adenocarcinoma of the stomach predicts shorter survival after curative resection. | Motojima K et al |
| 12960136 | 2003 | Expression of her-2/neu on acute lymphoblastic leukemias: implications for the development of immunotherapeutic approaches. | Müller MR et al |
| 12759537 | 2003 | Prognostic role of apoptotic, Bcl-2, c-erbB-2 and p53 tumor markers in salivary gland malignancies. | Nagler RM et al |
| 12455054 | 2003 | Correlation between encoded protein overexpression and copy number of the HER2 gene with survival in non-small cell lung cancer. | Nakamura H et al |
| 10329415 | 1999 | Identification of a novel promoter and exons of the c-ERBB-2 gene. | Nezu M et al |
| 12874758 | 2003 | Molecular and immunohistochemical analysis of HER2/neu oncogene in synovial sarcoma. | Nuciforo PG et al |
| 10880430 | 2000 | The ErbB signaling network: receptor heterodimerization in development and cancer. | Olayioye MA et al |
| 14734462 | 2004 | Synchronous overexpression of epidermal growth factor receptor and HER2-neu protein is a predictor of poor outcome in patients with stage I non-small cell lung cancer. | Onn A et al |
| 12072561 | 2002 | Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. | Ozcelik C et al |
| 1681519 | 1991 | G to A polymorphism at amino acid codon 655 of the human erbB-2/HER2 gene. | Papewalis J et al |
| 10466438 | 1999 | Primary cancer of the fallopian tube with transitional differentiation. Clinical and pathological assessment of 6 cases. | Rabczyński JK et al |
| 15385115 | 2004 | The prognostic and predictive value of immunohistochemically detected HER-2/neu overexpression in 361 patients with ovarian cancer: a multicenter study. | Riener EK et al |
| 11786427 | 2002 | Expression and gene copy number analysis of ERBB2 oncogene in prostate cancer. | Savinainen KJ et al |
| 10772679 | 2000 | Pathogenesis of Paget's disease: epidermal heregulin-alpha, motility factor, and the HER receptor family. | Schelfhout VR et al |
| 21152867 | 2011 | A novel recombinant immuno-tBid with a furin site effectively suppresses the growth of HER2-positive osteosarcoma cells in vitro. | Shan LQ et al |
| 14566826 | 2003 | HER-2 and TOP2A coamplification in urinary bladder cancer. | Simon R et al |
| 3798106 | 1987 | Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. | Slamon DJ et al |
| 15457249 | 2004 | Lung cancer: intragenic ERBB2 kinase mutations in tumours. | Stephens P et al |
| 20385184 | 2010 | The role of HER2 in cancer therapy and targeted drug delivery. | Tai W et al |
| 14639106 | 2003 | HER-2/neu protein expression and gene alteration in stage I-IIIA non-small-cell lung cancer: a study of 140 cases using a combination of high throughput tissue microarray, immunohistochemistry, and fluorescent in situ hybridization. | Tan D et al |
| 1348293 | 1992 | Clinicopathological significance of c-erbB-2 protein expression in human gastric carcinoma. | Tateishi M et al |
| 8816440 | 1996 | A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. | Tzahar E et al |
| 20371674 | 2010 | Genetic and expression analysis of HER-2 and EGFR genes in salivary duct carcinoma: empirical and therapeutic significance. | Williams MD et al |
| 9815530 | 1997 | Strong correlation between c-erbB-2 overexpression and overall survival of patients with oral squamous cell carcinoma. | Xia W et al |
| 10699071 | 2000 | Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk. | Xie D et al |
| 11252954 | 2001 | Untangling the ErbB signalling network. | Yarden Y et al |
| 18087285 | 2008 | Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. | Yoshikawa D et al |
| 14607699 | 2002 | Expression of c-erbB-2 oncogene protein, epidermal growth factor receptor, and TGF-beta1 in human pancreatic ductal adenocarcinoma. | Zhang L et al |
| 12544770 | 2003 | Her-2/neu expression in osteosarcoma increases risk of lung metastasis and can be associated with gene amplification. | Zhou H et al |
Other Information
Locus ID:
NCBI: 2064
MIM: 164870
HGNC: 3430
Ensembl: ENSG00000141736
Variants:
dbSNP: 2064
ClinVar: 2064
TCGA: ENSG00000141736
COSMIC: ERBB2
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA131301952 | gefitinib | Chemical | Pathway | associated | |||
| PA134687924 | erlotinib | Chemical | Pathway | associated | |||
| PA152241907 | lapatinib | Chemical | LabelAnnotation, MultilinkAnnotation, Pathway, VipGene | associated | 23220880, 26570998 | ||
| PA164746311 | everolimus | Chemical | LabelAnnotation | associated | |||
| PA164747170 | fulvestrant | Chemical | LabelAnnotation | associated | |||
| PA164920420 | olaparib | Chemical | LabelAnnotation | associated | |||
| PA165110439 | ixabepilone | Chemical | LabelAnnotation | associated | |||
| PA165290933 | pertuzumab | Chemical | LabelAnnotation, VipGene | associated | |||
| PA165291472 | neratinib | Chemical | LabelAnnotation, MultilinkAnnotation, VipGene | associated | 23220880 | ||
| PA165958441 | trastuzumab emtansine | Chemical | LabelAnnotation, VipGene | associated | |||
| PA166153469 | palbociclib | Chemical | LabelAnnotation | associated | |||
| PA166153470 | ribociclib | Chemical | LabelAnnotation | associated | |||
| PA166153471 | abemaciclib | Chemical | LabelAnnotation | associated | |||
| PA166182723 | eribulin | Chemical | LabelAnnotation | associated | |||
| PA166182740 | talazoparib | Chemical | LabelAnnotation | associated | |||
| PA166184523 | alpelisib | Chemical | LabelAnnotation | associated | |||
| PA166184566 | tipiracil / trifluridine | Chemical | LabelAnnotation | associated | |||
| PA166190621 | fam-trastuzumab deruxtecan-nxki | Chemical | LabelAnnotation | associated | |||
| PA29988 | JAK1 | Gene | Pathway | associated | |||
| PA33308 | PIK3CA | Gene | Pathway | associated | |||
| PA33309 | PIK3CB | Gene | Pathway | associated | |||
| PA33310 | PIK3CD | Gene | Pathway | associated | |||
| PA33311 | PIK3CG | Gene | Pathway | associated | |||
| PA33312 | PIK3R1 | Gene | Pathway | associated | |||
| PA33313 | PIK3R2 | Gene | Pathway | associated | |||
| PA33314 | PIK3R3 | Gene | Pathway | associated | |||
| PA33392 | PLCG1 | Gene | Pathway | associated | |||
| PA33393 | PLCG2 | Gene | Pathway | associated | |||
| PA443560 | Breast Neoplasms | Disease | ClinicalAnnotation, MultilinkAnnotation, VipGene | associated | PD | 15140287, 17693647, 23220880, 30071039 | |
| PA443937 | Drug Toxicity | Disease | ClinicalAnnotation | associated | PD | 17693647 | |
| PA448803 | carboplatin | Chemical | ClinicalAnnotation | associated | PD | 30071039 | |
| PA449383 | docetaxel | Chemical | ClinicalAnnotation | associated | PD | 30071039 | |
| PA451743 | trastuzumab | Chemical | ClinicalAnnotation, LabelAnnotation, MultilinkAnnotation, VipGene | associated | PD | 17693647, 30071039, 9788323 |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 36650045 | 2024 | Expression and correlation of PD-L1 and HER2 in oesophageal squamous cell carcinoma. | 0 |
| 37406458 | 2024 | HER2/ ERBB2 Immunohistochemical Expression and Copy Number Status in Ovarian Mucinous Tumors. | 1 |
| 37537510 | 2024 | Clinical significance of CD166 and HER-2 in different types of gastric cancer. | 0 |
| 37555322 | 2024 | A systematic review and meta-analysis for human epidermal growth factor receptor 2 on upper tract urothelial carcinoma patients. | 0 |
| 37672800 | 2024 | Rare HER2 L796P missense mutation promotes the growth and oncogenic signaling in breast cancer cells. | 0 |
| 37914528 | 2024 | Mesothelin expression in gynecologic carcinosarcoma: clinicopathological significance and correlation with HER2 expression. | 0 |
| 38029652 | 2024 | Molecular landscape of ERBB2/HER2 gene amplification among patients with gynecologic malignancies; clinical implications and future directions. | 4 |
| 38109791 | 2024 | Site-specific glycosylation analysis of epidermal growth factor receptor 2 (ErbB2): exploring structure and function toward therapeutic targeting. | 0 |
| 38219954 | 2024 | Characterizing the Genomic Landscape of the Micropapillary Subtype of Urothelial Carcinoma of the Bladder Harboring Activating Extracellular Mutations of ERBB2. | 0 |
| 38291340 | 2024 | Mitochondrial HER2 stimulates respiration and promotes tumorigenicity. | 0 |
| 38335419 | 2024 | HER2-positive is an independent indicator for predicting pathological complete response to neoadjuvant therapy and Ki67-changed after neoadjuvant chemotherapy predicts favorable prognosis in Chinese women with locally advanced breast cancer. | 0 |
| 38335502 | 2024 | ERBB2-amplified lobular breast carcinoma exhibits concomitant CDK12 co-amplification associated with poor prognostic features. | 1 |
| 38351535 | 2024 | miRNA-449c-5p regulates the JAK-STAT pathway in inhibiting cell proliferation and invasion in human breast cancer cells by targeting ERBB2. | 1 |
| 38356054 | 2024 | Potential Role of Nrf2, HER2, and ALDH in Cancer Stem Cells: A Narrative Review. | 0 |
| 38374017 | 2024 | HER2 Affects the Biological Behaviours of Bladder Cancer Cells and is Closely Associated with the Progression and Prognosis of Bladder Cancer. | 0 |
Citation
Luca Braccioli ; Marilena V Iorio ; Patrizia Casalini
ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))
Atlas Genet Cytogenet Oncol Haematol. 2011-05-01
Online version: http://atlasgeneticsoncology.org/gene/162/
Historical Card
2004-12-01 ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)) by Patrizia Casalini,Marilena V Iorio Affiliation
Molecular Targeting Unit, Experimental Oncology Dept., Istituto Nazionale Tumori, Via Venezian, 1, 20133 Milano, Italy
