HER2/neu

Receptor tyrosine-protein kinase erbB-2, also known as CD340 (cluster of differentiation 340), proto-oncogene Neu, Erbb2 (rodent), or ERBB2 (human), is a protein that in humans is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene isolated from avian genome. It is also frequently called HER2 (from human epidermal growth factor receptor 2) or HER2/neu.[5][6][7]

ERBB2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1MFG, 1MFL, 1MW4, 1N8Z, 1QR1, 1S78, 2A91, 2JWA, 2KS1, 2L4K, 3BE1, 3H3B, 3N85, 3PP0, 3RCD, 3MZW, 3WLW, 3WSQ, 4GFU, 4HRL, 4HRM, 4HRN, 2N2A
Identifiers
Aliases	ERBB2, CD340, HER-2, HER-2/neu, HER2, MLN 19, NEU, NGL, TKR1, erb-b2 receptor tyrosine kinase 2
External IDs	OMIM: 164870 MGI: 95410 HomoloGene: 3273 GeneCards: ERBB2
EC number	2.7.10.1
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17q12 Start 39,687,914 bp[1] End 39,730,426 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11 61.75 cM|11 D Start 98,412,470 bp[2] End 98,437,716 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • ErbB-3 class receptor binding • transferase activity • nucleotide binding • protein kinase activity • protein dimerization activity • growth factor binding • RNA polymerase I core binding • kinase activity • protein C-terminus binding • GO:0001948 protein binding • identical protein binding • protein heterodimerization activity • transmembrane receptor protein tyrosine kinase activity • protein tyrosine kinase activity • protein phosphatase binding • ATP binding • transmembrane signaling receptor activity • Ras guanyl-nucleotide exchange factor activity • phosphatidylinositol-4,5-bisphosphate 3-kinase activity • receptor tyrosine kinase Cellular component • integral component of membrane • membrane • myelin • receptor complex • cell membrane • basolateral plasma membrane • apical plasma membrane • perinuclear region of cytoplasm • endosome membrane • cytoplasmic vesicle • cell nucleus • cytoplasm • cytosol • integral component of plasma membrane • basal plasma membrane Biological process • positive regulation of protein phosphorylation • peripheral nervous system development • regulation of transcription, DNA-templated • negative regulation of immature T cell proliferation in thymus • positive regulation of MAP kinase activity • phosphorylation • transmembrane receptor protein tyrosine kinase signaling pathway • positive regulation of epithelial cell proliferation • cellular response to growth factor stimulus • wound healing • oligodendrocyte differentiation • regulation of angiogenesis • positive regulation of translation • transcription, DNA-templated • nervous system development • MAPK cascade • protein phosphorylation • heart development • cell surface receptor signaling pathway • GO:0032320, GO:0032321, GO:0032855, GO:0043089, GO:0032854 positive regulation of GTPase activity • positive regulation of cell growth • regulation of microtubule-based process • neuromuscular junction development • regulation of ERK1 and ERK2 cascade • myelination • autophosphorylation • phosphatidylinositol 3-kinase signaling • positive regulation of transcription from RNA polymerase I promoter • cellular proliferation • positive regulation of transcription from RNA polymerase III promoter • motor neuron axon guidance • enzyme linked receptor protein signaling pathway • signal transduction • positive regulation of cell adhesion • positive regulation of protein targeting to membrane • ERBB2 signaling pathway • phosphatidylinositol phosphorylation • positive regulation of gene expression • peptidyl-tyrosine phosphorylation • regulation of cell motility • cellular response to epidermal growth factor stimulus • regulation of transcription from RNA polymerase II promoter • negative regulation of ERBB signaling pathway • positive regulation of protein kinase B signaling • negative regulation of signal transduction • cell differentiation • negative regulation of apoptotic process • positive regulation of ERK1 and ERK2 cascade • GO:0007243 intracellular signal transduction • positive regulation of cell proliferation • neuron differentiation • positive regulation of MAPK cascade Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	2064	13866
Ensembl	ENSG00000141736	ENSMUSG00000062312
UniProt	P04626	P70424
RefSeq (mRNA)	NM_001005862 NM_001289936 NM_001289937 NM_001289938 NM_004448	NM_001003817
RefSeq (protein)	NP_001005862 NP_001276865 NP_001276866 NP_001276867 NP_004439 NP_001369711 NP_001369712 NP_001369713 NP_001369714 NP_001369715 NP_001369716 NP_001369717 NP_001369718 NP_001369719 NP_001369720 NP_001369721 NP_001369722 NP_001369723 NP_001369724 NP_001369725 NP_001369726 NP_001369727 NP_001369728 NP_001369729 NP_001369730 NP_001369731 NP_001369732 NP_001369733 NP_001369734 NP_001369735	NP_001003817
Location (UCSC)	Chr 17: 39.69 – 39.73 Mb	Chr 11: 98.41 – 98.44 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Amplification or over-expression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. In recent years the protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients.[8]

Name

HER2 is so named because it has a similar structure to human epidermal growth factor receptor, or HER1. Neu is so named because it was derived from a rodent glioblastoma cell line, a type of neural tumor. ErbB-2 was named for its similarity to ErbB (avian erythroblastosis oncogene B), the oncogene later found to code for EGFR. Molecular cloning of the gene showed that HER2, Neu, and ErbB-2 are all encoded by the same orthologs.[9]

Gene

ERBB2, a known proto-oncogene, is located at the long arm of human chromosome 17 (17q12).

Function

The ErbB family consists of four plasma membrane-bound receptor tyrosine kinases. One of which is erbB-2, and the other members being epidermal growth factor receptor, erbB-3 (neuregulin-binding; lacks kinase domain), and erbB-4. All four contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular domain that can interact with a multitude of signaling molecules and exhibit both ligand-dependent and ligand-independent activity. Notably, no ligands for HER2 have yet been identified.[10][11] HER2 can heterodimerise with any of the other three receptors and is considered to be the preferred dimerisation partner of the other ErbB receptors.[12]

Dimerisation results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways.

Signal transduction

Signaling pathways activated by HER2 include:[13]

• mitogen-activated protein kinase (MAPK)
• phosphoinositide 3-kinase (PI3K/Akt)
• phospholipase C γ
• protein kinase C (PKC)
• Signal transducer and activator of transcription (STAT)

In summary, signaling through the ErbB family of receptors promotes cell proliferation and opposes apoptosis, and therefore must be tightly regulated to prevent uncontrolled cell growth from occurring.

Clinical significance

Cancer

Amplification, also known as the over-expression of the ERBB2 gene, occurs in approximately 15-30% of breast cancers.[8][14] It is strongly associated with increased disease recurrence and a poor prognosis; however, drug agents targeting HER2 in breast cancer have significantly positively altered the otherwise poor-prognosis natural history of HER2-positive breast cancer.[15] Over-expression is also known to occur in ovarian,[16] stomach, adenocarcinoma of the lung[17] and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma,[18][19] e.g. HER-2 is over-expressed in approximately 7-34% of patients with gastric cancer[20][21] and in 30% of salivary duct carcinomas.[22]

HER2 is colocalised and most of the time, coamplified with the gene GRB7, which is a proto-oncogene associated with breast, testicular germ cell, gastric, and esophageal tumours.

HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.[23][24]

Evidence has also implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.[25]

Mutations

Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression. HER2 is found in a variety of tumours and some of these tumours carry point mutations in the sequence specifying the transmembrane domain of HER2. Substitution of a valine for a glutamic acid in the transmembrane domain can result in the constitutive dimerisation of this protein in the absence of a ligand.[26]

HER2 mutations have been found in non-small-cell lung cancers (NSCLC) and can direct treatment.[27]

As a drug target

HER2 is the target of the monoclonal antibody trastuzumab (marketed as Herceptin). Trastuzumab is effective only in cancers where HER2 is over-expressed. One year of trastuzumab therapy is recommended for all patients with HER2-positive breast cancer who are also receiving chemotherapy.[28] Twelve months of trastuzumab therapy is optimal. Randomized trials have demonstrated no additional benefit beyond 12 months, whereas 6 months has been shown to be inferior to 12. Trastuzumab is administered intravenously weekly or every 3 weeks.[29]

An important downstream effect of trastuzumab binding to HER2 is an increase in p27, a protein that halts cell proliferation.[30] Another monoclonal antibody, Pertuzumab, which inhibits dimerisation of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012.

As of November 2015, there are a number of ongoing and recently completed clinical trials of novel targeted agents for HER2+ metastatic breast cancer, e.g. margetuximab.[31]

Additionally, NeuVax (Galena Biopharma) is a peptide-based immunotherapy that directs "killer" T cells to target and destroy cancer cells that express HER2. It has entered phase 3 clinical trials.

It has been found that patients with ER+ (Estrogen receptor positive)/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.[32]

Over-expression of HER2 can also be suppressed by the amplification of other genes. Research is currently being conducted to discover which genes may have this desired effect.

The expression of HER2 is regulated by signaling through estrogen receptors. Normally, estradiol and tamoxifen acting through the estrogen receptor down-regulate the expression of HER2. However, when the ratio of the coactivator AIB-3 exceeds that of the corepressor PAX2, the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant breast cancer.[33][34]

Her2 and Her3 distribution on a breast cell, (3D Dual Colour Super Resolution Microscopy SPDMphymod / LIMON, marked with Alexa 488 and 568)

Diagnostics

Cancer biopsy

HER2 testing is performed in breast cancer patients to assess prognosis and to determine suitability for trastuzumab therapy. It is important that trastuzumab is restricted to HER2-positive individuals as it is expensive and has been associated with cardiac toxicity.[35] For HER2-negative tumours, the risks of trastuzumab clearly outweigh the benefits.

Her 2 staining on patient breast cancer tissue identified as stage 3

The staining is seen as a cell membrane with continuous brown color.

Tests are usually performed on breast biopsy samples obtained by either fine-needle aspiration, core needle biopsy, vacuum-assisted breast biopsy, or surgical excision. Immunohistochemistry is used to measure the amount of HER2 protein present in the sample. Examples of this assay include HercepTest, Dako, Glostrup, and Denmark. The sample is given a score based on the cell membrane staining pattern.

Immunohistochemistry

Score[36][37]	Status[36][37]	Pattern
0	HER2 negative (not present)	Negative for HER2 protein expression.[38]
1+		Weak or incomplete membrane staining in any tumor cells.[38]
2+	Borderline/Equivocal	Complete membrane staining that is either nonuniform or weak in intensity, but has circumferential distribution in at least 10% of cells.[37][38] or Uniform intense membrane staining in 30% or less of tumor cells.[38]
3+	HER2 positive	Uniform intense membrane staining of more than 30% of invasive tumor cells.[37][38]

Specimens with equivocal IHC results should then be validated using fluorescence in situ hybridisation (FISH). FISH can be used to measure the number of copies of the gene which are present and is thought to be more reliable than IHC.[39]

Serum

The extracellular domain of HER2 can be shed from the surface of tumour cells and enter the circulation. Measurement of serum HER2 by enzyme-linked immunosorbent assay (ELISA) offers a far less invasive method of determining HER2 status than a biopsy and consequently has been extensively investigated. Results so far have suggested that changes in serum HER2 concentrations may be useful in predicting response to trastuzumab therapy.[40] However, its ability to determine eligibility for trastuzumab therapy is less clear.[41]

Interactions

HER2/neu has been shown to interact with:

• CTNNB1,[42][43][44]
• DLG4,[45]
• Erbin,[46][47][48]
• GRB2,[49][50][51]
• HSP90AA1,[52][53]
• IL6ST,[54]
• MUC1,[55][56]
• PICK1[46] and
• PIK3R2,[57]
• PLCG1,[58][59] and
• SHC1.[49][51][60]

See also

• Ann Marie Rogers, campaigned for UK NHS to provide Herceptin
• SkBr3 Cell Line, over-expresses HER2

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Further reading

• Ross JS, Fletcher JA, Linette GP, Stec J, Clark E, Ayers M, Symmans WF, Pusztai L, Bloom KJ (2003). "The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy". The Oncologist. 8 (4): 307–25. doi:10.1634/theoncologist.8-4-307. PMID 12897328.
• Zhou BP, Hung MC (October 2003). "Dysregulation of cellular signaling by HER2/neu in breast cancer". Seminars in Oncology. 30 (5 Suppl 16): 38–48. doi:10.1053/j.seminoncol.2003.08.006. PMID 14613025.
• Ménard S, Casalini P, Campiglio M, Pupa SM, Tagliabue E (December 2004). "Role of HER2/neu in tumor progression and therapy". Cellular and Molecular Life Sciences. 61 (23): 2965–78. doi:10.1007/s00018-004-4277-7. PMID 15583858.
• Becker JC, Muller-Tidow C, Serve H, Domschke W, Pohle T (June 2006). "Role of receptor tyrosine kinases in gastric cancer: new targets for a selective therapy". World Journal of Gastroenterology. 12 (21): 3297–305. doi:10.3748/wjg.v12.i21.3297. PMC 4087885. PMID 16733844.
• Laudadio J, Quigley DI, Tubbs R, Wolff DJ (January 2007). "HER2 testing: a review of detection methodologies and their clinical performance". Expert Review of Molecular Diagnostics. 7 (1): 53–64. doi:10.1586/14737159.7.1.53. PMID 17187484.
• Bianchi F, Tagliabue E, Ménard S, Campiglio M (March 2007). "Fhit expression protects against HER2-driven breast tumor development: unraveling the molecular interconnections". Cell Cycle. 6 (6): 643–6. doi:10.4161/cc.6.6.4033. PMID 17374991.

External links

• ERBB2 expression across human cancerous and healthy tissues
• AACR Cancer Concepts Factsheet on HER2
• Breast Friends for Life Network - A South African Breast Cancer Support Forum for HER2 Positive Women
• HerceptinR : Herceptin Resistance Database for Understanding Mechanism of Resistance in Breast Cancer Patients. Sci. Rep. 4:4483
• Receptor,+erbB-2 at the US National Library of Medicine Medical Subject Headings (MeSH)
• PDBe-KB provides an overview of all the structure information available in the PDB for Human Receptor tyrosine-protein kinase erbB-2