HER2/neu

Erb-b2 receptor tyrosine kinase 2
PDB rendering based on 1n8z (of Fab fragment of trastuzumab (blue) bound to the extracellular domain of HER2 (beige)).
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1MFG​, 1MFL​, 1MW4​, 1N8Z​, 1OVC​, 1QR1​, 1S78​, 2A91​, 2JWA​, 2KS1​, 2L4K​, 3BE1​, 3H3B​, 3MZW​, 3N85​, 3PP0​, 3RCD​, 3WLW​, 3WSQ​, 4GFU​, 4HRL​, 4HRM​, 4HRN​
Identifiers
Symbols	ERBB2 ; CD340; HER-2; HER-2/neu; HER2; MLN 19; NEU; NGL; TKR1
External IDs	OMIM: 164870 MGI: 95410 HomoloGene: 3273 ChEMBL: 1824 GeneCards: ERBB2 Gene
EC number	2.7.10.1
Gene ontology Molecular function • RNA polymerase I core binding • protein tyrosine kinase activity • transmembrane receptor protein tyrosine kinase activity • receptor signaling protein tyrosine kinase activity • transmembrane signaling receptor activity • protein binding • ATP binding • protein C-terminus binding • growth factor binding • protein phosphatase binding • identical protein binding • ErbB-3 class receptor binding • protein heterodimerization activity • protein dimerization activity Cellular component • nucleus • cytoplasm • plasma membrane • endosome membrane • integral component of membrane • basolateral plasma membrane • apical plasma membrane • cytoplasmic vesicle • myelin sheath • receptor complex • perinuclear region of cytoplasm Biological process • MAPK cascade • activation of MAPKK activity • positive regulation of protein phosphorylation • transcription, DNA-templated • protein phosphorylation • signal transduction • cell surface receptor signaling pathway • enzyme linked receptor protein signaling pathway • transmembrane receptor protein tyrosine kinase signaling pathway • epidermal growth factor receptor signaling pathway • small GTPase mediated signal transduction • Ras protein signal transduction • axon guidance • peripheral nervous system development • heart development • neuromuscular junction development • motor neuron axon guidance • cell proliferation • insulin receptor signaling pathway • fibroblast growth factor receptor signaling pathway • phosphatidylinositol 3-kinase signaling • peptidyl-tyrosine phosphorylation • positive regulation of cell growth • regulation of microtubule-based process • negative regulation of immature T cell proliferation in thymus • Fc-epsilon receptor signaling pathway • wound healing • myelination • positive regulation of MAP kinase activity • positive regulation of GTPase activity • innate immune response • positive regulation of translation • regulation of angiogenesis • positive regulation of cell adhesion • positive regulation of transcription from RNA polymerase I promoter • positive regulation of transcription from RNA polymerase III promoter • protein autophosphorylation • vascular endothelial growth factor receptor signaling pathway • neurotrophin TRK receptor signaling pathway • phosphatidylinositol-mediated signaling • oligodendrocyte differentiation • positive regulation of epithelial cell proliferation • regulation of ERK1 and ERK2 cascade • cellular response to growth factor stimulus • positive regulation of protein targeting to membrane Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2064	13866
Ensembl	ENSG00000141736	ENSMUSG00000062312
UniProt	P04626	P70424
RefSeq (mRNA)	NM_001005862	NM_001003817
RefSeq (protein)	NP_001005862	NP_001003817
Location (UCSC)	Chr 17: 39.69 – 39.73 Mb	Chr 11: 98.41 – 98.44 Mb
PubMed search

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, which is also frequently called HER2 (from human epidermal growth factor receptor 2) or HER2/neu.

HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Amplification or overexpression 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.^[1]

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.^[2]

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. HER2 can heterodimerise with any of the other three receptors and is considered to be the preferred dimerisation partner of the other ErbB receptors.^[3]

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:^[4]

• 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.

HER2 and cancer

Amplification or over-expression of the ERBB2 gene occurs in approximately 15-30% of breast cancers.^[1][5] It is strongly associated with increased disease recurrence and a poor prognosis.^[6] Over-expression is also known to occur in ovarian, stomach, and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma.^[7][8] eg. HER-2 is overexpressed in approximately 7-34% of patients with gastric cancer^{[9] [10]} and in 30% of salivary duct carcinomas.^[11]

HER2 is co-localized, and, most of the time, co-amplified 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.^[12][13]

Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.^[14]

HER2 variations/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 tumors and some of these tumors 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 dimerization of this protein in the absence of a ligand.

HER2 mutations have been found in non-small-cell lung cancers (NSCLC) and can direct treatment.^[15]

Drugs targeting HER2

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.^[16] An important downstream effect of trastuzumab binding to HER2 is an increase in p27, a protein that halts cell proliferation.^[17] Another monoclonal antibody, Pertuzumab, which inhibits dimerization of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012.

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.^[18]

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.^[19][20]

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

HER2 testing

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.^[21] For HER2-negative tumours, the risks of trastuzumab clearly outweigh the benefits.

HER2 testing on tumor

Tests are usually performed on 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. Alternatively, fluorescence in situ hybridisation (FISH) can be used to measure the number of copies of the gene which are present.

HER2 testing on 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.^[22] However, its ability to determine eligibility for trastuzumab therapy is less clear.^[23]

HER2 interactions

HER2/neu has been shown to interact with:

• CTNNB1,^[24][25][26]
• DLG4,^[27]
• Erbin,^[28][29][30]
• GRB2,^[31][32][33]
• HSP90AA1,^[34][35]
• IL6ST,^[36]
• MUC1,^[37][38]
• PICK1^[28] and
• PIK3R2,^[39]
• PLCG1,^[40][41] and
• SHC1.^[31][33][42]

See also

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

References

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22. Ali SM, Carney WP, Esteva FJ, Fornier M, Harris L, Köstler WJ, Lotz JP, Luftner D, Pichon MF, Lipton A (Sep 2008). "Serum HER-2/neu and relative resistance to trastuzumab-based therapy in patients with metastatic breast cancer". Cancer 113 (6): 1294–301. doi:10.1002/cncr.23689. PMID 18661530.
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24. Schroeder JA, Adriance MC, McConnell EJ, Thompson MC, Pockaj B, Gendler SJ (Jun 2002). "ErbB-beta-catenin complexes are associated with human infiltrating ductal breast and murine mammary tumor virus (MMTV)-Wnt-1 and MMTV-c-Neu transgenic carcinomas". The Journal of Biological Chemistry 277 (25): 22692–8. doi:10.1074/jbc.M201975200. PMID 11950845.
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Further reading

• Xiaojun Xia, Junhua Mai, Rong Xu, Jorge Enrique Tovar Perez, Maria L. Guevara, Qi Shen, Chaofeng Mu, Hui-Ying Tung, David B. Corry, Scott E. Evans, Xuewu Liu, Mauro Ferrari, Zhiqiang Zhang, Xian Chang Li, Rong-fu Wang, Haifa Shen. (2015). Porous Silicon Microparticle Potentiates Anti-Tumor Immunity by Enhancing Cross-Presentation and Inducing Type I Interferon Response. Cell Reports,; doi:10.1016/j.celrep.2015.04.009
• 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 (Oct 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 (Dec 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 (Jun 2006). "Role of receptor tyrosine kinases in gastric cancer: new targets for a selective therapy". World Journal of Gastroenterology 12 (21): 3297–305. PMID 16733844.
• Laudadio J, Quigley DI, Tubbs R, Wolff DJ (Jan 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 (Mar 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)