|V-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)|
PDB rendering based on 1n8z.
|Symbols||ERBB2 (; CD340; HER-2; HER-2/neu; HER2; MLN 19; NEU; NGL; TKR1)|
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
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. The ERBB2 gene is also frequently called HER2 (from human epidermal growth factor receptor 2) or HER2/neu.
HER2 is a member of the epidermal growth factor receptor (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 approx. 30% of breast cancer patients.
ERBB2, a known proto-oncogene, is 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 orthologs.
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. Dimerisation results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways. The other members of the family are Epidermal growth factor receptor, erbB-3 (neuregulin-binding; lacks kinase domain), and erbB-4.
Signaling pathways activated by HER2 include:
- 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. It is strongly associated with increased disease recurrence and a poor prognosis. Over-expression is also known to occur in ovarian, stomach, and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma.
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.
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.
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. 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.
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.
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.
HER2 testing is performed in breast cancer patients to assess prognosis and to determine suitability for trastazumab therapy. It is important that trastazumab is restricted to HER2-positive individuals as it is expensive and has been associated with cardiac toxicity. For HER2-negative tumours, the risks of trastazumab 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 trastazumab therapy. However, its ability to determine eligibility for trastazumab therapy is less clear.
HER2/neu has been shown to interact with:
- Mitri Z, Constantine T, O'Regan R (2012). "The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy". Chemother Res Pract 2012: 743193. doi:10.1155/2012/743193. PMC 3539433. PMID 23320171.
- Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U (December 1985). "Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene". Science 230 (4730): 1132–9. doi:10.1126/science.2999974. PMID 2999974.
- Olayioye MA (2001). "Update on HER-2 as a target for cancer therapy: Intracellular signaling pathways of ErbB2/HER-2 and family members". Breast Cancer Res 3 (6): 385–389. doi:10.1186/bcr327. PMC 138705. PMID 11737890.
- Roy V, Perez EA (November 2009). "Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer". Oncologist 14 (11): 1061–9. doi:10.1634/theoncologist.2009-0142. PMID 19887469.
- Burstein HJ (October 2005). "The distinctive nature of HER2-positive breast cancers". N. Engl. J. Med. 353 (16): 1652–4. doi:10.1056/NEJMp058197. PMID 16236735.
- Tan M, Yu D (2007). "Molecular mechanisms of erbB2-mediated breast cancer chemoresistance". Adv. Exp. Med. Biol. 608: 119–29. PMID 17993237.
- Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S. (2008). "Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu". Int J Gynaecol Obstet 102 (2): 128–31. doi:10.1016/j.ijgo.2008.04.008. PMID 18555254.
- Nagy P, Jenei A, Kirsch AK, Szöllosi J, Damjanovich S, Jovin TM (June 1999). "Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy". J. Cell. Sci. 112 (11): 1733–41. PMID 10318765.
- Kaufmann R, Müller P, Hildenbrand G, Hausmann M, Cremer C (April 2011). "Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy". J Microsc 242 (1): 46–54. doi:10.1111/j.1365-2818.2010.03436.x. PMID 21118230.
- XF Le, Franz Pruefer, Robert Bast. (2005). "HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways". Cell Cycle 4 (1): 87–95. doi:10.4161/cc.4.1.1360. PMID 15611642.
- Loi S, Sotiriou C, Haibe-Kains B, Lallemand F, Conus NM, Piccart MJ, Speed TP, McArthur GA (2009). "Gene expression profiling identifies activated growth factor signaling in poor prognosis (Luminal-B) estrogen receptor positive breast cancer". BMC Med Genomics 2: 37. doi:10.1186/1755-8794-2-37. PMC 2706265. PMID 19552798. Lay summary – ScienceDaily.
- "Study sheds new light on tamoxifen resistance". Cordis News. Cordis. 2008-11-13. Retrieved 2008-11-14.
- Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS (November 2008). "ERBB2 regulation by Estrogen Receptor-Pax2 determines tamoxifen response". Nature 456 (7222): 663–6. doi:10.1038/nature07483. PMC 2920208. PMID 19005469.
- Yonesaka K, Zejnullahu K, Okamoto I, et al. (September 2011). "Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab". Sci Transl Med 3 (99): 99ra86. doi:10.1126/scitranslmed.3002442. PMC 3268675. PMID 21900593.
- Telli ML, Hunt SA, Carlson RW, Guardino AE (August 2007). "Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility". J. Clin. Oncol. 25 (23): 3525–33. doi:10.1200/JCO.2007.11.0106. PMID 17687157.
- Ali SM, Carney WP, Esteva FJ, Fornier M, Harris L, Köstler WJ, Lotz JP, Luftner D, Pichon MF, Lipton A (September 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.
- Lennon S, Barton C, Banken L, Gianni L, Marty M, Baselga J, Leyland-Jones B (April 2009). "Utility of serum HER2 extracellular domain assessment in clinical decision making: pooled analysis of four trials of trastuzumab in metastatic breast cancer". J. Clin. Oncol. 27 (10): 1685–93. doi:10.1200/JCO.2008.16.8351. PMID 19255335.
- Schroeder JA, Adriance MC, McConnell EJ, Thompson MC, Pockaj B, Gendler SJ (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". J. Biol. Chem. 277 (25): 22692–8. doi:10.1074/jbc.M201975200. PMID 11950845.
- Bonvini P, An WG, Rosolen A, Nguyen P, Trepel J, Garcia de Herreros A, Dunach M, Neckers LM (2001). "Geldanamycin abrogates ErbB2 association with proteasome-resistant beta-catenin in melanoma cells, increases beta-catenin-E-cadherin association, and decreases beta-catenin-sensitive transcription". Cancer Res. 61 (4): 1671–7. PMID 11245482.
- Kanai Y, Ochiai A, Shibata T, Oyama T, Ushijima S, Akimoto S, Hirohashi S (1995). "c-erbB-2 gene product directly associates with beta-catenin and plakoglobin". Biochem. Biophys. Res. Commun. 208 (3): 1067–72. doi:10.1006/bbrc.1995.1443. PMID 7702605.
- Huang YZ, Won S, Ali DW, Wang Q, Tanowitz M, Du QS, Pelkey KA, Yang DJ, Xiong WC, Salter MW, Mei L (2000). "Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses". Neuron 26 (2): 443–55. PMID 10839362.
- Jaulin-Bastard F, Saito H, Le Bivic A, Ollendorff V, Marchetto S, Birnbaum D, Borg JP (2001). "The ERBB2/HER2 receptor differentially interacts with ERBIN and PICK1 PSD-95/DLG/ZO-1 domain proteins". J. Biol. Chem. 276 (18): 15256–63. doi:10.1074/jbc.M010032200. PMID 11278603.
- Bilder D, Birnbaum D, Borg JP, Bryant P, Huigbretse J, Jansen E, Kennedy MB, Labouesse M, Legouis R, Mechler B, Perrimon N, Petit M, Sinha P (2000). "Collective nomenclature for LAP proteins". Nat. Cell Biol. 2 (7): E114. doi:10.1038/35017119.
- Huang YZ, Zang M, Xiong WC, Luo Z, Mei L (2003). "Erbin suppresses the MAP kinase pathway". J. Biol. Chem. 278 (2): 1108–14. doi:10.1074/jbc.M205413200. PMID 12379659.
- Schulze WX, Deng L, Mann M (2005). "Phosphotyrosine interactome of the ErbB-receptor kinase family". Mol. Syst. Biol. 1: 2005.0008. doi:10.1038/msb4100012. PMC 1681463. PMID 16729043.
- Bourguignon LY, Zhu H, Zhou B, Diedrich F, Singleton PA, Hung MC (2001). "Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185(HER2) and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth". J. Biol. Chem. 276 (52): 48679–92. doi:10.1074/jbc.M106759200. PMID 11606575.
- Olayioye MA, Graus-Porta D, Beerli RR, Rohrer J, Gay B, Hynes NE (1998). "ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner". Mol. Cell. Biol. 18 (9): 5042–51. PMC 109089. PMID 9710588.
- Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M, Yarden Y, Neckers L (2001). "Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90". J. Biol. Chem. 276 (5): 3702–8. doi:10.1074/jbc.M006864200. PMID 11071886.
- Jeong JH, An JY, Kwon YT, Li LY, Lee YJ (2008). "Quercetin-induced ubiquitination and down-regulation of Her-2/neu". J. Cell. Biochem. 105 (2): 585–95. doi:10.1002/jcb.21859. PMC 2575035. PMID 18655187.
- Grant SL, Hammacher A, Douglas AM, Goss GA, Mansfield RK, Heath JK, Begley CG (2002). "An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells". Oncogene 21 (3): 460–74. doi:10.1038/sj.onc.1205100. PMID 11821958.
- Li Y, Yu WH, Ren J, Chen W, Huang L, Kharbanda S, Loda M, Kufe D (2003). "Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein". Mol. Cancer Res. 1 (10): 765–75. PMID 12939402.
- Schroeder JA, Thompson MC, Gardner MM, Gendler SJ (2001). "Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland". J. Biol. Chem. 276 (16): 13057–64. doi:10.1074/jbc.M011248200. PMID 11278868.
- Gout I, Dhand R, Panayotou G, Fry MJ, Hiles I, Otsu M, Waterfield MD (1992). "Expression and characterization of the p85 subunit of the phosphatidylinositol 3-kinase complex and a related p85 beta protein by using the baculovirus expression system". Biochem. J. 288 ( Pt 2): 395–405. PMC 1132024. PMID 1334406.
- Peles E, Levy RB, Or E, Ullrich A, Yarden Y (1991). "Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma". EMBO J. 10 (8): 2077–86. PMC 452891. PMID 1676673.
- Arteaga CL, Johnson MD, Todderud G, Coffey RJ, Carpenter G, Page DL (1991). "Elevated content of the tyrosine kinase substrate phospholipase C-gamma 1 in primary human breast carcinomas". Proc. Natl. Acad. Sci. U.S.A. 88 (23): 10435–9. PMC 52943. PMID 1683701.
- Wong L, Deb TB, Thompson SA, Wells A, Johnson GR (1999). "A differential requirement for the COOH-terminal region of the epidermal growth factor (EGF) receptor in amphiregulin and EGF mitogenic signaling". J. Biol. Chem. 274 (13): 8900–9. PMID 10085134.
- 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.
- 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.
- 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.
- 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:10.1586/1473718.104.22.168. PMID 17187484.
- 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.
- 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.
- 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 US National Library of Medicine Medical Subject Headings (MeSH)