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
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
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 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.[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]

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:

See also

References

  1. 1 2 Mitri Z, Constantine T, O'Regan R (2012). "The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy". Chemotherapy Research and Practice 2012: 743193. doi:10.1155/2012/743193. PMC 3539433. PMID 23320171.
  2. ↑ Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U (Dec 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.
  3. ↑ 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 Research 3 (6): 385–9. doi:10.1186/bcr327. PMC 138705. PMID 11737890.
  4. ↑ Roy V, Perez EA (Nov 2009). "Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer". The Oncologist 14 (11): 1061–9. doi:10.1634/theoncologist.2009-0142. PMID 19887469.
  5. ↑ Burstein HJ (Oct 2005). "The distinctive nature of HER2-positive breast cancers". The New England Journal of Medicine 353 (16): 1652–4. doi:10.1056/NEJMp058197. PMID 16236735.
  6. ↑ Tan M, Yu D (2007). "Molecular mechanisms of erbB2-mediated breast cancer chemoresistance". Advances in Experimental Medicine and Biology 608: 119–29. doi:10.1007/978-0-387-74039-3_9. PMID 17993237.
  7. ↑ Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S (Aug 2008). "Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu". International Journal of Gynaecology and Obstetrics 102 (2): 128–31. doi:10.1016/j.ijgo.2008.04.008. PMID 18555254.
  8. ↑ Buza N, Roque DM, Santin AD (Mar 2014). "HER2/neu in Endometrial Cancer: A Promising Therapeutic Target With Diagnostic Challenges". Archives of Pathology & Laboratory Medicine 138 (3): 343–50. doi:10.5858/arpa.2012-0416-RA. PMID 24576030.
  9. ↑ Rüschoff J, Hanna W, Bilous M, Hofmann M, Osamura RY, Penault-Llorca F, van de Vijver M, Viale G (May 2012). "HER2 testing in gastric cancer: a practical approach". Modern Pathology 25 (5): 637–50. doi:10.1038/modpathol.2011.198. PMID 22222640.
  10. ↑ Meza-Junco J, Au HJ, Sawyer MB (2011). "Critical appraisal of trastuzumab in treatment of advanced stomach cancer". Cancer Management and Research 3 (3): 57–64. doi:10.2147/CMAR.S12698. PMC 3085240. PMID 21556317.
  11. ↑ Chiosea SI, Williams L, Griffith CC, Thompson LD, Weinreb I, Bauman JE, Luvison A, Roy S, Seethala RR, Nikiforova MN (Jun 2015). "Molecular characterization of apocrine salivary duct carcinoma". The American Journal of Surgical Pathology 39 (6): 744–52. doi:10.1097/PAS.0000000000000410. PMID 25723113.
  12. ↑ Nagy P, Jenei A, Kirsch AK, Szöllosi J, Damjanovich S, Jovin TM (Jun 1999). "Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy". Journal of Cell Science 112 (11): 1733–41. PMID 10318765.
  13. ↑ Kaufmann R, Müller P, Hildenbrand G, Hausmann M, Cremer C (Apr 2011). "Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy". Journal of Microscopy 242 (1): 46–54. doi:10.1111/j.1365-2818.2010.03436.x. PMID 21118230.
  14. ↑ Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, Ercan D, Rogers A, Roncalli M, Takeda M, Fujisaka Y, Philips J, Shimizu T, Maenishi O, Cho Y, Sun J, Destro A, Taira K, Takeda K, Okabe T, Swanson J, Itoh H, Takada M, Lifshits E, Okuno K, Engelman JA, Shivdasani RA, Nishio K, Fukuoka M, Varella-Garcia M, Nakagawa K, Jänne PA (Sep 2011). "Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab". Science Translational Medicine 3 (99): 99ra86. doi:10.1126/scitranslmed.3002442. PMC 3268675. PMID 21900593.
  15. ↑ Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives.
  16. ↑ Mates M, Fletcher GG, Freedman OC, Eisen A, Gandhi S, Trudeau ME, Dent SF (Mar 2015). "Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline". Current Oncology 22 (Suppl 1): S114–22. doi:10.3747/co.22.2322. PMC 4381787. PMID 25848335.
  17. ↑ Le XF, Pruefer F, Bast RC (Jan 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.
  18. ↑ 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 Medical Genomics 2: 37. doi:10.1186/1755-8794-2-37. PMC 2706265. PMID 19552798. Lay summary – ScienceDaily.
  19. ↑ "Study sheds new light on tamoxifen resistance". Cordis News. Cordis. 2008-11-13. Retrieved 2008-11-14.
  20. ↑ Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS (Dec 2008). "Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen". Nature 456 (7222): 663–6. doi:10.1038/nature07483. PMC 2920208. PMID 19005469.
  21. ↑ Telli ML, Hunt SA, Carlson RW, Guardino AE (Aug 2007). "Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility". Journal of Clinical Oncology 25 (23): 3525–33. doi:10.1200/JCO.2007.11.0106. PMID 17687157.
  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.
  23. ↑ Lennon S, Barton C, Banken L, Gianni L, Marty M, Baselga J, Leyland-Jones B (Apr 2009). "Utility of serum HER2 extracellular domain assessment in clinical decision making: pooled analysis of four trials of trastuzumab in metastatic breast cancer". Journal of Clinical Oncology 27 (10): 1685–93. doi:10.1200/JCO.2008.16.8351. PMID 19255335.
  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.
  25. ↑ Bonvini P, An WG, Rosolen A, Nguyen P, Trepel J, Garcia de Herreros A, Dunach M, Neckers LM (Feb 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 Research 61 (4): 1671–7. PMID 11245482.
  26. ↑ Kanai Y, Ochiai A, Shibata T, Oyama T, Ushijima S, Akimoto S, Hirohashi S (Mar 1995). "c-erbB-2 gene product directly associates with beta-catenin and plakoglobin". Biochemical and Biophysical Research Communications 208 (3): 1067–72. doi:10.1006/bbrc.1995.1443. PMID 7702605.
  27. ↑ Huang YZ, Won S, Ali DW, Wang Q, Tanowitz M, Du QS, Pelkey KA, Yang DJ, Xiong WC, Salter MW, Mei L (May 2000). "Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses". Neuron 26 (2): 443–55. doi:10.1016/s0896-6273(00)81176-9. PMID 10839362.
  28. 1 2 Jaulin-Bastard F, Saito H, Le Bivic A, Ollendorff V, Marchetto S, Birnbaum D, Borg JP (May 2001). "The ERBB2/HER2 receptor differentially interacts with ERBIN and PICK1 PSD-95/DLG/ZO-1 domain proteins". The Journal of Biological Chemistry 276 (18): 15256–63. doi:10.1074/jbc.M010032200. PMID 11278603.
  29. ↑ 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 (Jul 2000). "Collective nomenclature for LAP proteins". Nature Cell Biology 2 (7): E114. doi:10.1038/35017119.
  30. ↑ Huang YZ, Zang M, Xiong WC, Luo Z, Mei L (Jan 2003). "Erbin suppresses the MAP kinase pathway". The Journal of Biological Chemistry 278 (2): 1108–14. doi:10.1074/jbc.M205413200. PMID 12379659.
  31. 1 2 Schulze WX, Deng L, Mann M (2005). "Phosphotyrosine interactome of the ErbB-receptor kinase family". Molecular Systems Biology 1: 2005.0008. doi:10.1038/msb4100012. PMC 1681463. PMID 16729043.
  32. ↑ Bourguignon LY, Zhu H, Zhou B, Diedrich F, Singleton PA, Hung MC (Dec 2001). "Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185(HER2) and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth". The Journal of Biological Chemistry 276 (52): 48679–92. doi:10.1074/jbc.M106759200. PMID 11606575.
  33. 1 2 Olayioye MA, Graus-Porta D, Beerli RR, Rohrer J, Gay B, Hynes NE (Sep 1998). "ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner". Molecular and Cellular Biology 18 (9): 5042–51. doi:10.1128/mcb.18.9.5042. PMC 109089. PMID 9710588.
  34. ↑ Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M, Yarden Y, Neckers L (Feb 2001). "Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90". The Journal of Biological Chemistry 276 (5): 3702–8. doi:10.1074/jbc.M006864200. PMID 11071886.
  35. ↑ Jeong JH, An JY, Kwon YT, Li LY, Lee YJ (Oct 2008). "Quercetin-induced ubiquitination and down-regulation of Her-2/neu". Journal of Cellular Biochemistry 105 (2): 585–95. doi:10.1002/jcb.21859. PMC 2575035. PMID 18655187.
  36. ↑ Grant SL, Hammacher A, Douglas AM, Goss GA, Mansfield RK, Heath JK, Begley CG (Jan 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.
  37. ↑ Li Y, Yu WH, Ren J, Chen W, Huang L, Kharbanda S, Loda M, Kufe D (Aug 2003). "Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein". Molecular Cancer Research 1 (10): 765–75. PMID 12939402.
  38. ↑ Schroeder JA, Thompson MC, Gardner MM, Gendler SJ (Apr 2001). "Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland". The Journal of Biological Chemistry 276 (16): 13057–64. doi:10.1074/jbc.M011248200. PMID 11278868.
  39. ↑ Gout I, Dhand R, Panayotou G, Fry MJ, Hiles I, Otsu M, Waterfield MD (Dec 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". The Biochemical Journal 288 (2): 395–405. doi:10.1042/bj2880395. PMC 1132024. PMID 1334406.
  40. ↑ Peles E, Levy RB, Or E, Ullrich A, Yarden Y (Aug 1991). "Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma". The EMBO Journal 10 (8): 2077–86. PMC 452891. PMID 1676673.
  41. ↑ Arteaga CL, Johnson MD, Todderud G, Coffey RJ, Carpenter G, Page DL (Dec 1991). "Elevated content of the tyrosine kinase substrate phospholipase C-gamma 1 in primary human breast carcinomas". Proceedings of the National Academy of Sciences of the United States of America 88 (23): 10435–9. doi:10.1073/pnas.88.23.10435. PMC 52943. PMID 1683701.
  42. ↑ Wong L, Deb TB, Thompson SA, Wells A, Johnson GR (Mar 1999). "A differential requirement for the COOH-terminal region of the epidermal growth factor (EGF) receptor in amphiregulin and EGF mitogenic signaling". The Journal of Biological Chemistry 274 (13): 8900–9. doi:10.1074/jbc.274.13.8900. PMID 10085134.

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

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