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 ERBB2gene, which is also frequently called HER2 (from human epidermal growth factor receptor 2) or HER2/neu.
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. 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, 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.
Dimerisation results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways.
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.
HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.
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 antibodytrastuzumab (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.
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.
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 coactivatorAIB-3 exceeds that of the corepressorPAX2, the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant breast cancer.
Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.
Her2 and Her3 distribution on a breast cell, (3D Dual Colour Super Resolution Microscopy SPDMphymod / LIMON,marked with Alexa 488 and 568)
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.
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.
^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 Obstet102 (2): 128–31. doi:10.1016/j.ijgo.2008.04.008. PMID18555254.
^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. PMID10318765.
^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 Microsc242 (1): 46–54. doi:10.1111/j.1365-2818.2010.03436.x. PMID21118230.
^XF Le, Franz Pruefer, Robert Bast. (2005). "HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways". Cell Cycle4 (1): 87–95. doi:10.4161/cc.4.1.1360. PMID15611642.
^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. PMID17687157.
^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". Cancer113 (6): 1294–301. doi:10.1002/cncr.23689. PMID18661530.
^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. PMID19255335.
^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. PMID11950845.
^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. PMID11245482.
^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. PMID7702605.
^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". Neuron26 (2): 443–55. doi:10.1016/s0896-6273(00)81176-9. PMID10839362.
^ abJaulin-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. PMID11278603.
^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.
^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. PMID11071886.
^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". Oncogene21 (3): 460–74. doi:10.1038/sj.onc.1205100. PMID11821958.
^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. PMID12939402.
^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. PMID11278868.
^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. doi:10.1074/jbc.274.13.8900. PMID10085134.