HER2
Template:PBB HER2 (Human Epidermal Growth Factor Receptor 2) also known as Neu, ErbB-2, CD340 (cluster of differentiation 340) or p185 is a protein that in humans is encoded by the ERBB2 gene. HER2 is a member of the epidermal growth factor receptor (EGFR/ErbB) family. Amplification or over-expression of this gene has been shown to play an important role in the pathogenesis and progression of certain aggressive types of breast cancer and in recent years it has evolved to become an important biomarker and target of therapy for the disease.
Function
Gene
HER2 is encoded by ERBB2, a known proto-oncogene located at the long arm of human chromosome 17 (17q12). HER2 is 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. Gene cloning showed that HER2, Neu, and ErbB-2 are all encoded by the same gene.[1]
Protein
The ErbB family is composed of four plasma membrane-bound receptor tyrosine kinases. 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.[2] 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:[3]
- 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 30% of breast cancers. It is strongly associated with increased disease recurrence and a worse prognosis.[4] Over-expression is also known to occur in ovarian, stomach, and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma.[5]
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.[6][7]
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. An important downstream effect of trastuzumab binding to HER2 is an increase in p27, a protein that halts cell proliferation.[8] 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 is revealed 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.[9]
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.[10][11]
Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.[12]
Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression. As stated the 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. The resulting substitution of a valine for a glutamic acid results in the constitutive dimerisation of this protein in the absence of a ligand.
HER2 testing
HER2 testing is performed in breast cancer patients to assess prognosis and to determine suitability for Herceptin therapy. It is important that Herceptin is restricted to HER2-positive individuals as it is expensive and has been associated with cardiac toxicity.[13] For HER2-negative tumours, the risks of Herceptin clearly outweigh the benefits.
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.
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 Herceptin therapy.[14] However, its ability to determine eligibility for Herceptin therapy is less clear.[15]
HER2 interactions
HER2 has been shown to interact with Beta-catenin,[16][17][18] Glycoprotein 130,[19] PLCG1,[20][21] Erbin,[22][23][24] MUC1,[25][26] Grb2,[27][28][29] Heat shock protein 90kDa alpha (cytosolic), member A1,[30][31] DLG4,[32] PIK3R2,[33] PICK1[22] and SHC1.[27][29][34]
See also
References
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Further reading
- Ross JS, Fletcher JA, Linette GP; et al. (2003). "The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy". Oncologist. 8 (4): 307–25. doi:10.1634/theoncologist.8-4-307. PMID 12897328.
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(help)CS1 maint: multiple names: authors list (link) - Zhou BP, Hung MC (2003). "Dysregulation of cellular signaling by HER2/neu in breast cancer". Semin. Oncol. 30 (5 Suppl 16): 38–48. doi:10.1053/j.seminoncol.2003.08.006. PMID 14613025.
- Ménard S, Casalini P, Campiglio M; et al. (2005). "Role of HER2/neu in tumor progression and therapy". Cell. Mol. Life Sci. 61 (23): 2965–78. doi:10.1007/s00018-004-4277-7. PMID 15583858.
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(help)CS1 maint: multiple names: authors list (link) - Becker JC, Muller-Tidow C, Serve H; et al. (2006). "Role of receptor tyrosine kinases in gastric cancer: new targets for a selective therapy". World J. Gastroenterol. 12 (21): 3297–305. PMID 16733844.
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(help)CS1 maint: multiple names: authors list (link) - Laudadio J, Quigley DI, Tubbs R, Wolff DJ (2007). "HER2 testing: a review of detection methodologies and their clinical performance". Expert Rev. Mol. Diagn. 7 (1): 53–64. doi:10.1586/14737159.7.1.53. PMID 17187484.
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: CS1 maint: multiple names: authors list (link) - Bianchi F, Tagliabue E, Ménard S, Campiglio M (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.
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: CS1 maint: multiple names: authors list (link) - Del Bimbo A., Meoni M., Pala P. (2010). "Accurate evaluation of HER-2 amplification in FISH images". Imaging Systems and Techniques (IST), 2010 IEEE International Conference on: 407–10. doi:10.1109/IST.2010.5548461. ISBN 978-1-4244-6492-0.
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External links
- ERBB2 expression across human cancerous and healthy tissues
- AACR Cancer Concepts Factsheet on HER2
- Her2/neu Vaccine Protects Against Tumor Growth
- Chimeric molecules and Methods of Use
- Breast Friends for Life Network - A South African Breast Cancer Support Forum for HER2 Positive Women
- Receptor,+erbB-2 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)