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 

Identity

HGNC
ERBB2
LOCATION
17q12
IMAGE
Atlas Image
LEGEND
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
LOCUSID
2064
ALIAS
CD340,HER-2,HER-2/neu,HER2,MLN
FUSION GENES
Show Gene Fusions

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.

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.

Proteins

Atlas Image
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.

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.

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
Osteosarcoma
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.

Bibliography

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Other Information

Locus ID:

NCBI: 2064
MIM: 164870
HGNC: 3430
Ensembl: ENSG00000141736

Variants:

dbSNP: 2064
ClinVar: 2064
TCGA: ENSG00000141736
COSMIC: ERBB2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000141736ENST00000269571P04626
ENSG00000141736ENST00000269571X5DNK3
ENSG00000141736ENST00000406381P04626
ENSG00000141736ENST00000445658B4DTR1
ENSG00000141736ENST00000541774P04626
ENSG00000141736ENST00000578199F5H1T4
ENSG00000141736ENST00000578373J3QL83
ENSG00000141736ENST00000578502J3QRX1
ENSG00000141736ENST00000578709J3QLV2
ENSG00000141736ENST00000580074J3KTI5
ENSG00000141736ENST00000582648J3KRI9
ENSG00000141736ENST00000582818J3QRJ7
ENSG00000141736ENST00000584450J3QLU9
ENSG00000141736ENST00000584601P04626

Expression (GTEx)

0
50
100
150
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

Pathways

PathwaySourceExternal ID
ErbB signaling pathwayKEGGko04012
Calcium signaling pathwayKEGGko04020
Focal adhesionKEGGko04510
Adherens junctionKEGGko04520
Tight junctionKEGGko04530
Pancreatic cancerKEGGko05212
Endometrial cancerKEGGko05213
Prostate cancerKEGGko05215
Bladder cancerKEGGko05219
Non-small cell lung cancerKEGGko05223
ErbB signaling pathwayKEGGhsa04012
Calcium signaling pathwayKEGGhsa04020
Focal adhesionKEGGhsa04510
Adherens junctionKEGGhsa04520
Tight junctionKEGGhsa04530
Pathways in cancerKEGGhsa05200
Pancreatic cancerKEGGhsa05212
Endometrial cancerKEGGhsa05213
Prostate cancerKEGGhsa05215
Bladder cancerKEGGhsa05219
Non-small cell lung cancerKEGGhsa05223
HIF-1 signaling pathwayKEGGhsa04066
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Central carbon metabolism in cancerKEGGhsa05230
Central carbon metabolism in cancerKEGGko05230
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
GAB1 signalosomeREACTOMER-HSA-180292
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
Signaling by ERBB2REACTOMER-HSA-1227986
SHC1 events in ERBB2 signalingREACTOMER-HSA-1250196
GRB2 events in ERBB2 signalingREACTOMER-HSA-1963640
PI3K events in ERBB2 signalingREACTOMER-HSA-1963642
PLCG1 events in ERBB2 signalingREACTOMER-HSA-1251932
GRB7 events in ERBB2 signalingREACTOMER-HSA-1306955
Downregulation of ERBB2:ERBB3 signalingREACTOMER-HSA-1358803
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Semaphorin interactionsREACTOMER-HSA-373755
Sema4D in semaphorin signalingREACTOMER-HSA-400685
Sema4D induced cell migration and growth-cone collapseREACTOMER-HSA-416572
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
ERBB2 Regulates Cell MotilityREACTOMER-HSA-6785631
ERBB2 Activates PTK6 SignalingREACTOMER-HSA-8847993
Signaling by PTK6REACTOMER-HSA-8848021
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
Platinum drug resistanceKEGGko01524
Endocrine resistanceKEGGko01522
Platinum drug resistanceKEGGhsa01524
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
Endocrine resistanceKEGGhsa01522
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factorsREACTOMER-HSA-8864260
TFAP2 (AP-2) family regulates transcription of growth factors and their receptorsREACTOMER-HSA-8866910
RET signalingREACTOMER-HSA-8853659
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224
Downregulation of ERBB2 signalingREACTOMER-HSA-8863795

Protein levels (Protein atlas)

Not detected
Low
Medium
High
cerebral cortex
cerebellum
hippocampus
caudate
thyroid gland
parathyroid gland
adrenal gland
nasopharynx
bronchus
lung
oral mucosa
salivary gland
esophagus
stomach 1
stomach 2
duodenum
small intestine
colon
rectum
liver
gallbladder
pancreas
kidney
urinary bladder
testis
epididymis
seminal vesicle
prostate
vagina
ovary
fallopian tube
endometrium 1
endometrium 2
cervix, uterine
placenta
breast
heart muscle
smooth muscle
skeletal muscle
soft tissue 1
soft tissue 2
adipose tissue
skin 1
skin 2
appendix
spleen
lymph node
tonsil
bone marrow

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA131301952gefitinibChemicalPathwayassociated
PA134687924erlotinibChemicalPathwayassociated
PA152241907lapatinibChemicalLabelAnnotation, MultilinkAnnotation, Pathway, VipGeneassociated23220880, 26570998
PA164746311everolimusChemicalLabelAnnotationassociated
PA164747170fulvestrantChemicalLabelAnnotationassociated
PA164920420olaparibChemicalLabelAnnotationassociated
PA165110439ixabepiloneChemicalLabelAnnotationassociated
PA165290933pertuzumabChemicalLabelAnnotation, VipGeneassociated
PA165291472neratinibChemicalLabelAnnotation, MultilinkAnnotation, VipGeneassociated23220880
PA165958441trastuzumab emtansineChemicalLabelAnnotation, VipGeneassociated
PA166153469palbociclibChemicalLabelAnnotationassociated
PA166153470ribociclibChemicalLabelAnnotationassociated
PA166153471abemaciclibChemicalLabelAnnotationassociated
PA166182723eribulinChemicalLabelAnnotationassociated
PA166182740talazoparibChemicalLabelAnnotationassociated
PA166184523alpelisibChemicalLabelAnnotationassociated
PA166184566tipiracil / trifluridineChemicalLabelAnnotationassociated
PA166190621fam-trastuzumab deruxtecan-nxkiChemicalLabelAnnotationassociated
PA29988JAK1GenePathwayassociated
PA33308PIK3CAGenePathwayassociated
PA33309PIK3CBGenePathwayassociated
PA33310PIK3CDGenePathwayassociated
PA33311PIK3CGGenePathwayassociated
PA33312PIK3R1GenePathwayassociated
PA33313PIK3R2GenePathwayassociated
PA33314PIK3R3GenePathwayassociated
PA33392PLCG1GenePathwayassociated
PA33393PLCG2GenePathwayassociated
PA443560Breast NeoplasmsDiseaseClinicalAnnotation, MultilinkAnnotation, VipGeneassociatedPD15140287, 17693647, 23220880, 30071039
PA443937Drug ToxicityDiseaseClinicalAnnotationassociatedPD17693647
PA448803carboplatinChemicalClinicalAnnotationassociatedPD30071039
PA449383docetaxelChemicalClinicalAnnotationassociatedPD30071039
PA451743trastuzumabChemicalClinicalAnnotation, LabelAnnotation, MultilinkAnnotation, VipGeneassociatedPD17693647, 30071039, 9788323

References

Pubmed IDYearTitleCitations
234709652013Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.633
194360382009Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer.573
255247982015The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study.448
126106292003Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab.425
221538902012Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.395
184087612008BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.377
196930112009Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment.349
128535642003The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation.347
247757122014Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer.325
213832832011RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer.285

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/erbb2

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 

Molecular Targeting Unit, Experimental Oncology Dept., Istituto Nazionale Tumori, Via Venezian, 1, 20133 Milano, Italy