HER2/neu

V-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)

PDB rendering based on 1n8z.
Identifiers
Symbols ERBB2; CD340; HER-2; HER-2/neu; HER2; MLN 19; NEU; NGL; TKR1
External IDs OMIM: 164870 MGI: 95410 HomoloGene: 3273 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 Q80Y89
RefSeq (mRNA) NM_001005862.1 NM_001003817.1
RefSeq (protein) NP_001005862.1 NP_001003817.1
Location (UCSC) Chr 17:
37.84 – 37.88 Mb		 Chr 11:
98.27 – 98.3 Mb
PubMed search [2] [3]

HER-2 (Human Epidermal growth factor Receptor 2) also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 (cluster of differentiation 340) or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Overexpression of this gene is correlated with higher aggressiveness in breast cancers. It is a member of the ErbB protein family, more commonly known as the epidermal growth factor receptor family.

Contents

Function

HER2 is a cell membrane surface-bound receptor tyrosine kinase and is normally involved in the signal transduction pathways leading to cell growth and differentiation. It is encoded within the genome by HER2/neu, a known proto-oncogene. HER2 is thought to be an orphan receptor, with none of the EGF family of ligands able to activate it. However, ErbB receptors dimerise on ligand binding, and HER2 is the preferential dimerisation partner of other members of the ErbB family.[1] The HER2 gene is a proto-oncogene located at the long arm of human chromosome 17(17q21-q22).[2]

HER2 and cancer

Approximately 30% of breast cancers have an amplification of the HER2/neu gene or overexpression of its protein product.[3] Overexpression of this receptor in breast cancer is associated with increased disease recurrence and worse prognosis. Because of its prognostic role as well as its ability to predict response to trastuzumab (US brand name: Herceptin) (see below), breast tumors are routinely checked for overexpression of HER2/neu. Overexpression also occurs in other cancer such as ovarian cancer, stomach cancer, and biologically aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma.[4]

The oncogene neu is so-named because it was derived from a rodent glioblastoma cell line, which is a type of neural tumor, hence 'neu.' HER2 is named because it has a similar structure to human epidermal growth factor receptor, or HER1. ErbB2 was named for its similarity to ErbB (avian erythroblastosis oncogene B), the oncogene later found to code for EGFR. Gene cloning showed that neu, HER2, and ErbB2 are the same.

HER2 is co-localized, and, thus, most of the time, co-amplified with the gene GRB7, which is also a proto-oncogene (active in, e.g., breast cancer, testicular germ cell tumor, gastric cancer, and esophageal cancer). It is revealed that patients with ER+/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.[5]

HER2 protein is known to form clusters in cell membranes that might play a role in tumorigenesis.[6][7]

Drugs targeting HER2

In clinical usage, HER2/neu is important as the target of the monoclonal antibody trastuzumab (marketed as Herceptin). Trastuzumab is effective only in cancers where the HER2/neu receptor is overexpressed. One of the downstream effects of trastuzimab binding to HER2 is an increase in p27, a protein that halts cell proliferation.[8]

Overexpression of the HER2 gene can also be suppressed by the amplification of other genes. Research is currently being conducted to discover which disregulated genes may have this desired effect. Another monoclonal antibody, Pertuzumab [4], which inhibits dimerization of HER2 and HER3 receptors, is in advanced clinical trials.

The expression of HER2/ERBB2 protein is regulated by estrogen receptors. Furthermore, estradiol and tamoxifen acting through the estrogen receptor normally down-regulates the expression of HER2/ERBB2. However, when the ratio of the coactivator AIB-3 exceeds that of the corepressor PAX2, the expression of HER2/ERBB2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant breast cancer.[9][10]

Recent evidence has implicated signalling via HER2/neu in resistance to the EGFR-targeted cancer drug cetuximab.[11]


Interactions

HER2/neu has been shown to interact with Beta-catenin,[12][13][14] Glycoprotein 130,[15] PLCG1,[16][17] Erbin,[18][19][20] MUC1,[21][22] Grb2,[23][24][25] Heat shock protein 90kDa alpha (cytosolic), member A1,[26][27] DLG4,[28] PIK3R2,[29] PICK1[18] and SHC1.[23][25][30]

References

  1. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=138705. 
  2. ^ Coussens L; Yang-Feng, TL; Liao, YC; Chen, E; Gray, A; McGrath, J; Seeburg, PH; Libermann, TA et al. (1985). "Tyrosine Kinase Receptor with Extensive Homology to EGF Receptor Shares Chromosomal Location with neu Oncogene". Science 230 (4730): 1132–1139. doi:10.1126/science.2999974. PMID 2999974. 
  3. ^ "Entrez Gene: ERBB2 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2064. 
  4. ^ 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. 
  5. ^ Estrogen Receptor Status of HER2+ Breast Cancer Correlates With Response to Anti-HER Therapies. ScienceDaily (May 6, 2010)[1]
  6. ^ Nagy, P., Jenei, A. Kirsch, A.K. Szollosi, J., Damjanovich, S. & Jovin, T.M.(1999): Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy, J. Cell Sci. 112, 1733-1741
  7. ^ Rainer Kaufmann, Patrick Müller, Georg Hildenbrand, Michael Hausmann & Christoph Cremer (2010): Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy, Journal of Microscopy 2010, doi: 10.1111/j.1365-2818.2010.03436.x
  8. ^ 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. 
  9. ^ "Study sheds new light on tamoxifen resistance". Cordis News. Cordis. 2008-11-13. http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=30093. Retrieved 2008-11-14. 
  10. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2920208. 
  11. ^ Yonesaka, K.; Zejnullahu, K.; Okamoto, I.; Satoh, T.; Cappuzzo, F.; Souglakos, J.; Ercan, D.; Rogers, A. et al. (2011). "Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab". Science Translational Medicine 3 (99): 99ra86–99ra86. doi:10.1126/scitranslmed.3002442. ISSN 1946-6234. 
  12. ^ Schroeder, Joyce A; Adriance Melissa C, McConnell Elizabeth J, Thompson Melissa C, Pockaj Barbara, Gendler Sandra J (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". J. Biol. Chem. (United States) 277 (25): 22692–8. doi:10.1074/jbc.M201975200. ISSN 0021-9258. PMID 11950845. 
  13. ^ Bonvini, P; An W G, Rosolen A, Nguyen P, Trepel J, Garcia de Herreros A, Dunach M, Neckers L M (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 Res. (United States) 61 (4): 1671–7. ISSN 0008-5472. PMID 11245482. 
  14. ^ 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". Biochem. Biophys. Res. Commun. (UNITED STATES) 208 (3): 1067–72. doi:10.1006/bbrc.1995.1443. ISSN 0006-291X. PMID 7702605. 
  15. ^ Grant, Susan L; Hammacher Annet, Douglas Andrea M, Goss Geraldine A, Mansfield Rachel K, Heath John K, Begley C Glenn (Jan. 2002). "An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells". Oncogene (England) 21 (3): 460–74. doi:10.1038/sj.onc.1205100. ISSN 0950-9232. PMID 11821958. 
  16. ^ Peles, E; Levy R B, Or E, Ullrich A, Yarden Y (Aug. 1991). "Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma". EMBO J. (ENGLAND) 10 (8): 2077–86. ISSN 0261-4189. PMC 452891. PMID 1676673. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=452891. 
  17. ^ Arteaga, C L; Johnson M D, Todderud G, Coffey R J, Carpenter G, Page D L (Dec. 1991). "Elevated content of the tyrosine kinase substrate phospholipase C-gamma 1 in primary human breast carcinomas". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 88 (23): 10435–9. doi:10.1073/pnas.88.23.10435. ISSN 0027-8424. PMC 52943. PMID 1683701. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=52943. 
  18. ^ a b Jaulin-Bastard, F; Saito H, Le Bivic A, Ollendorff V, Marchetto S, Birnbaum D, Borg J P (May. 2001). "The ERBB2/HER2 receptor differentially interacts with ERBIN and PICK1 PSD-95/DLG/ZO-1 domain proteins". J. Biol. Chem. (United States) 276 (18): 15256–63. doi:10.1074/jbc.M010032200. ISSN 0021-9258. PMID 11278603. 
  19. ^ Borg, J P; Marchetto S, Le Bivic A, Ollendorff V, Jaulin-Bastard F, Saito H, Fournier E, Adélaïde J, Margolis B, Birnbaum D (Jul. 2000). "ERBIN: a basolateral PDZ protein that interacts with the mammalian ERBB2/HER2 receptor". Nat. Cell Biol. (ENGLAND) 2 (7): 407–14. doi:10.1038/35017038. ISSN 1465-7392. PMID 10878805. 
  20. ^ Huang, Yang Z; Zang Mengwei, Xiong Wen C, Luo Zhijun, Mei Lin (Jan. 2003). "Erbin suppresses the MAP kinase pathway". J. Biol. Chem. (United States) 278 (2): 1108–14. doi:10.1074/jbc.M205413200. ISSN 0021-9258. PMID 12379659. 
  21. ^ Li, Yongqing; Yu Wei-Hsuan, Ren Jian, Chen Wen, Huang Lei, Kharbanda Surender, Loda Massimo, Kufe Donald (Aug. 2003). "Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein". Mol. Cancer Res. (United States) 1 (10): 765–75. ISSN 1541-7786. PMID 12939402. 
  22. ^ Schroeder, J A; Thompson M C, Gardner M M, Gendler S J (Apr. 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. (United States) 276 (16): 13057–64. doi:10.1074/jbc.M011248200. ISSN 0021-9258. PMID 11278868. 
  23. ^ a b Schulze, Waltraud X; Deng Lei, Mann Matthias (2005). "Phosphotyrosine interactome of the ErbB-receptor kinase family". Mol. Syst. Biol. (England) 1 (1): 2005.0008. doi:10.1038/msb4100012. PMC 1681463. PMID 16729043. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1681463. 
  24. ^ Bourguignon, L Y; Zhu H, Zhou B, Diedrich F, Singleton P A, Hung M C (Dec. 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. (United States) 276 (52): 48679–92. doi:10.1074/jbc.M106759200. ISSN 0021-9258. PMID 11606575. 
  25. ^ a b Olayioye, M A; Graus-Porta D, Beerli R R, Rohrer J, Gay B, Hynes N E (Sep. 1998). "ErbB-1 and ErbB-2 Acquire Distinct Signaling Properties Dependent upon Their Dimerization Partner". Mol. Cell. Biol. (UNITED STATES) 18 (9): 5042–51. ISSN 0270-7306. PMC 109089. PMID 9710588. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=109089. 
  26. ^ Xu, W; Mimnaugh E, Rosser M F, 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". J. Biol. Chem. (United States) 276 (5): 3702–8. doi:10.1074/jbc.M006864200. ISSN 0021-9258. PMID 11071886. 
  27. ^ Jeong, Jae-Hoon; An Jee Young, Kwon Yong Tae, Li Lu-Yuan, Lee Yong J (Oct. 2008). "Quercetin-induced ubiquitination and down-regulation of Her-2/neu". J. Cell. Biochem. (United States) 105 (2): 585–95. doi:10.1002/jcb.21859. PMC 2575035. PMID 18655187. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2575035. 
  28. ^ Huang, Y Z; Won S, Ali D W, Wang Q, Tanowitz M, Du Q S, Pelkey K A, Yang D J, Xiong W C, Salter M W, Mei L (May. 2000). "Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses". Neuron (UNITED STATES) 26 (2): 443–55. doi:10.1016/S0896-6273(00)81176-9. ISSN 0896-6273. PMID 10839362. 
  29. ^ Gout, I; Dhand R, Panayotou G, Fry M J, Hiles I, Otsu M, Waterfield M D (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". Biochem. J. (ENGLAND) 288 ( Pt 2) (Pt 2): 395–405. ISSN 0264-6021. PMC 1132024. PMID 1334406. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1132024. 
  30. ^ Wong, L; Deb T B, Thompson S A, Wells A, Johnson G R (Mar. 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. (UNITED STATES) 274 (13): 8900–9. doi:10.1074/jbc.274.13.8900. ISSN 0021-9258. PMID 10085134. 

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. 
  • 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:10.1586/14737159.7.1.53. 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. 

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Ligand
ONCO: c-Sis/PDGF · HGF
Receptor
TSP: CDH1
TSP: PTCH1
ONCO: ErbB/c-ErbB (HER2/neu, Her 3) - c-Met - c-Ret
ONCO: c-Kit - Flt3
Intracellular signaling P+Ps
ONCO: Beta-catenin · TSP: APC
TSP: SMAD2, SMAD4
TSP: PTEN · ONCO: c-Akt
Other/unknown
TSP: Maspin · ONCO: c-Src
Nucleus
TSP: p53 · pRb · WT1 · p16/p14arf · ONCO: CDK4 · Cyclin D · Cyclin E
ONCO: BRCA1 - BRCA2
TSP: VHL  · ONCO: CBL - MDM2
TSP: KLF6  · ONCO: AP-1 (c-Fos, c-Jun) - c-Myc
Mitochondria
Other/ungrouped

M: NEO

tsoc, mrkr

tumr, epon, para

drug (L1i/1e/V03)
Blood
Endocrine
Nervous system
Cardiovascular/
respiratory
Digestive
Reproductive/
urinary/
breast
CA 15-3 · erbB-2 receptor · erbB-3 receptor · Cathepsin D
General histology
Musculoskeletal

M: NEO

tsoc, mrkr

tumr, epon, para

drug (L1i/1e/V03)