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{{Infobox_gene}}
{{GNF_Protein_box
'''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]]. It is also frequently called '''''HER2''''' (from '''human epidermal growth factor receptor 2''') or '''''HER2/neu'''''.<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/2064|title=ERBB2 erb-b2 receptor tyrosine kinase 2 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2016-06-14}}</ref><ref>{{Cite web|url=https://ghr.nlm.nih.gov/gene/ERBB2|title=ERBB2|last=Reference|first=Genetics Home|website=Genetics Home Reference|access-date=2016-06-19}}</ref><ref>{{Cite book|url=https://books.google.com/books?id=xZoXBgAAQBAJ|title=Noninvasive Molecular Markers in Gynecologic Cancers|last=Barh|first=Debmalya|last2=Gunduz|first2=Mehmet | name-list-format = vanc |date=2015-01-22|publisher=CRC Press|page=427|isbn=9781466569393 }}</ref>
| image = Trastuzumab Fab-HER2 complex 1N8Z.png
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1n8z.


| Name = V-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)
HER2 is a member of the human [[epidermal growth factor receptor]] (HER/EGFR/ERBB) family. [[Gene duplication|Amplification]] or over-expression 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 (medicine)|biomarker]] and target of therapy for approximately 30% of [[breast cancer]] patients.<ref name="pmid23320171"/>
| HGNCid = 3430
| Symbol = ERBB2
| AltSymbols =; HER-2; HER-2/neu; HER2; NEU; NGL; TKR1; c-erb B2
| OMIM = 164870
| ECnumber = 
| Homologene = 3273
| MGIid = 95410
| GeneAtlas_image1 = PBB_GE_ERBB2_216836_s_at.png
| GeneAtlas_image2 = PBB_GE_ERBB2_210930_s_at.png
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{{GNF_GO|id=GO:0048015 |text = phosphoinositide-mediated signaling}} {{GNF_GO|id=GO:0050679 |text = positive regulation of epithelial cell proliferation}}
== Name ==
  | Orthologs = {{GNF_Ortholog_box
''HER2'' is so named because it has a similar structure to human epidermal growth factor receptor, or [[Epidermal growth factor receptor|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 [[Epidermal growth factor receptor|EGFR]]. Molecular cloning of the gene showed that HER2, Neu, and ErbB-2 are all encoded by the same [[Orthologous gene|ortholog]]s.<ref name="Coussens_1985">{{cite journal | vauthors = Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U | title = Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene | journal = Science | volume = 230 | issue = 4730 | pages = 1132–9 | date = December 1985 | pmid = 2999974 | doi = 10.1126/science.2999974 | bibcode = 1985Sci...230.1132C }}</ref>
    | Hs_EntrezGene = 2064
    | Hs_Ensembl = ENSG00000141736
    | Hs_RefseqProtein = NP_001005862
    | Hs_RefseqmRNA = NM_001005862
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 17
    | Hs_GenLoc_start = 35104766
    | Hs_GenLoc_end = 35138441
    | Hs_Uniprot = P04626
    | Mm_EntrezGene = 13866
    | Mm_Ensembl = ENSMUSG00000062312
    | Mm_RefseqmRNA = NM_001003817
    | Mm_RefseqProtein = NP_001003817
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 98228574
    | Mm_GenLoc_end = 98253806
    | Mm_Uniprot = Q80Y89
  }}
}}
{{SI}}
{{CMG}}


==Overview==
== Gene ==
'''V-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)''', also known as '''ERBB2''', is a human [[gene]].
''ERBB2'', a known [[proto-oncogene]], is located at the long arm of human [[chromosome 17]] (17q12).
<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{PBB_Summary
| section_title =
| summary_text = This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized.<ref>{{cite web | title = Entrez Gene: ERBB2 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2064| accessdate = }}</ref>
}}


== Function ==
The [[ErbB|ErbB family]] consists of four [[cell membrane|plasma membrane]]-bound [[receptor tyrosine kinase]]s.  One of which is erbB-2, and the other members being epidermal growth factor receptor, [[ERBB3|erbB-3]] (neuregulin-binding; lacks kinase domain), and [[ERBB4|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. Notably, no ligands for HER2 have yet been identified.<ref>{{cite journal | vauthors = Keshamouni VG, Mattingly RR, Reddy KB | title = Mechanism of 17-beta-estradiol-induced Erk1/2 activation in breast cancer cells. A role for HER2 AND PKC-delta | journal = The Journal of Biological Chemistry | volume = 277 | issue = 25 | pages = 22558–65 | date = June 2002 | pmid = 11960991 | doi = 10.1074/jbc.M202351200 }}</ref><ref>{{cite journal | vauthors = Rusnak DW, Affleck K, Cockerill SG, Stubberfield C, Harris R, Page M, Smith KJ, Guntrip SB, Carter MC, Shaw RJ, Jowett A, Stables J, Topley P, Wood ER, Brignola PS, Kadwell SH, Reep BR, Mullin RJ, Alligood KJ, Keith BR, Crosby RM, Murray DM, Knight WB, Gilmer TM, Lackey K | display-authors = 6 | title = The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer | journal = Cancer Research | volume = 61 | issue = 19 | pages = 7196–203 | date = October 2001 | pmid = 11585755 }}</ref> HER2 can heterodimerise with any of the other three receptors and is considered to be the preferred dimerisation partner of the other ErbB receptors.<ref name="Olayioye_2001">{{cite journal | vauthors = Olayioye MA | title = Update on HER-2 as a target for cancer therapy: intracellular signaling pathways of ErbB2/HER-2 and family members | journal = Breast Cancer Research | volume = 3 | issue = 6 | pages = 385–9 | year = 2001 | pmid = 11737890 | pmc = 138705 | doi = 10.1186/bcr327 }}</ref>


'''HER2/neu''' (also known as ErbB-2, {{gene|ERBB2}}) is a member of the [[ErbB]] protein family, more commonly known as the [[ErbB|epidermal growth factor receptor family]]. HER2/neu is notable for its role in the [[pathogenesis]] of [[breast cancer]] and as a target of treatment.  It is a cell membrane surface-bound [[receptor tyrosine kinase]] and is normally involved in the [[signal transduction]] pathways leading to cell growth and differentiation.  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.<ref name="Olayioye_2001">{{cite journal |author=Olayioye MA|title=Update on HER-2 as a target for cancer therapy: intracellular signaling pathways of ErbB2/HER-2 and family members|journal= Breast Cancer Res |volume= 3 |issue= 6 |pages= 385-389 |year= 2001|doi= 10.1186/bcr327 |pmid= 11737890}}</ref>  The ''HER2'' gene is a [[proto-oncogene]] located at the long arm of human chromosome 17(17q11.2-q12).
Dimerisation results in the [[autophosphorylation]] of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways.


Approximately 25-30 percent of breast cancers have an amplification of the ''HER2/neu'' gene or overexpression of its protein product. 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]] (see below), breast tumors are routinely checked for overexpression of HER2/neu.  Overexpression also occurs in other cancer such as ovarian cancer and stomach cancer. 
=== Signal transduction ===
Signaling pathways activated by HER2 include:<ref name="pmid19887469">{{cite journal | vauthors = Roy V, Perez EA | title = Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer | journal = The Oncologist | volume = 14 | issue = 11 | pages = 1061–9 | date = November 2009 | pmid = 19887469 | doi = 10.1634/theoncologist.2009-0142 }}</ref>
* [[mitogen-activated protein kinase]] (MAPK)
* [[phosphoinositide 3-kinase]] (PI3K/Akt)
* [[phospholipase C]] γ
* [[protein kinase C]] (PKC)
* [[STAT protein|Signal transducer and activator of transcription]] (STAT)


The [[oncogene]] ''neu'' is so-named because it was derived from a neuroglioblastoma cell line in rat.  HER2 is named because it has 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 were the same.  
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.


Clinically, HER2/neu is important as the target of the monoclonal [[antibody]] [[trastuzumab]] (marketed as Herceptin). Trastuzumab is only effective in breast cancer where the HER2/neu receptor is overexpressed.  
== HER2 and cancer ==
Amplification, also known as the over-expression of the ''ERBB2'' gene, occurs in approximately 15-30% of [[breast cancer]]s.<ref name="pmid23320171">{{cite journal | vauthors = Mitri Z, Constantine T, O'Regan R | title = The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy | journal = Chemotherapy Research and Practice | volume = 2012 | issue =  | pages = 743193 | year = 2012 | pmid = 23320171 | pmc = 3539433 | doi = 10.1155/2012/743193 }}</ref><ref name="pmid16236735">{{cite journal | vauthors = Burstein HJ | title = The distinctive nature of HER2-positive breast cancers | journal = The New England Journal of Medicine | volume = 353 | issue = 16 | pages = 1652–4 | date = October 2005 | pmid = 16236735 | doi = 10.1056/NEJMp058197 }}</ref> It is strongly associated with increased disease recurrence and a poor prognosis.<ref name="pmid17993237">{{cite journal | vauthors = Tan M, Yu D | title = Molecular mechanisms of erbB2-mediated breast cancer chemoresistance | journal = Advances in Experimental Medicine and Biology | volume = 608 | issue =  | pages = 119–29 | year = 2007 | pmid = 17993237 | doi = 10.1007/978-0-387-74039-3_9 | isbn = 978-0-387-74037-9 | series = Advances in Experimental Medicine and Biology }}</ref> Over-expression is also known to occur in ovarian,<ref>{{cite book |last1=Kumar |first=Vinay |last2=Abbas |first2=Abul |last3=Aster |first3=Jon | name-list-format = vanc | date=2013 |title=Robbins basic pathology |location=Philadelphia |publisher=Elsevier/Saunders |page=697 |isbn=9781437717815}}</ref> stomach, [[adenocarcinoma of the lung]]<ref>{{cite book |last1=Kumar |first=Vinay |last2=Abbas |first2=Abul |last3=Aster |first3=Jon | name-list-format = vanc | date=2013 |title=Robbins basic pathology |location=Philadelphia |publisher=Elsevier/Saunders |page=179 |isbn=9781437717815}}</ref>  and aggressive forms of uterine cancer, such as uterine serous [[endometrial carcinoma]],<ref>{{cite journal | vauthors = Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S | title = Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu | journal = International Journal of Gynaecology and Obstetrics | volume = 102 | issue = 2 | pages = 128–31 | date = August 2008 | pmid = 18555254 | doi = 10.1016/j.ijgo.2008.04.008 }}</ref><ref name=Buza2014>{{cite journal | vauthors = Buza N, Roque DM, Santin AD | title = HER2/neu in Endometrial Cancer: A Promising Therapeutic Target With Diagnostic Challenges | journal = Archives of Pathology & Laboratory Medicine | volume = 138 | issue = 3 | pages = 343–50 | date = March 2014 | pmid = 24576030 | doi = 10.5858/arpa.2012-0416-RA }}</ref> e.g. HER-2 is over-expressed in approximately 7-34% of patients with gastric cancer<ref name="Rüschoff2012">{{cite journal | vauthors = Rüschoff J, Hanna W, Bilous M, Hofmann M, Osamura RY, Penault-Llorca F, van de Vijver M, Viale G | title = HER2 testing in gastric cancer: a practical approach | journal = Modern Pathology | volume = 25 | issue = 5 | pages = 637–50 | date = May 2012 | pmid = 22222640 | doi = 10.1038/modpathol.2011.198 }}</ref><ref name="pmid21556317">{{cite journal | vauthors = Meza-Junco J, Au HJ, Sawyer MB | title = Critical appraisal of trastuzumab in treatment of advanced stomach cancer | journal = Cancer Management and Research | volume = 3 | issue = 3 | pages = 57–64 | year = 2011 | pmid = 21556317 | pmc = 3085240 | doi = 10.2147/CMAR.S12698 }}</ref> and in 30% of salivary duct carcinomas.<ref>{{cite journal | vauthors = Chiosea SI, Williams L, Griffith CC, Thompson LD, Weinreb I, Bauman JE, Luvison A, Roy S, Seethala RR, Nikiforova MN | title = Molecular characterization of apocrine salivary duct carcinoma | journal = The American Journal of Surgical Pathology | volume = 39 | issue = 6 | pages = 744–52 | date = June 2015 | pmid = 25723113 | doi = 10.1097/PAS.0000000000000410 }}</ref>


HER2 is co-localized, and thus most of the time co-amplified with the gene [[GRB7]], which is as well a proto-oncogene (active in e.g. breast cancer, testicular germ cell tumor, gastric cancer, and esophageal cancer).  
HER2 is co-localised, and, most of the time, co-amplified with the gene [[GRB7]], which is a proto-oncogene associated with breast, testicular germ cell, gastric, and eosophageal tumours.


The HER2 gene overexpression can be suppressed by the amplification of other genes and the use of the drug [[Herceptin]].  Research is currently being conducted to discover which disregulated genes may have this desired effect. Another monoclonal antibody, pertuzumab [http://www.healthvalue.net/EGFR-engl.html], which inhibits dimerization of HER2 and HER3 receptors, is in advanced clinical trials.
HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.<ref name="pmid10318765">{{cite journal | vauthors = Nagy P, Jenei A, Kirsch AK, Szöllosi J, Damjanovich S, Jovin TM | title = Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy | journal = Journal of Cell Science | volume = 112 | issue = 11 | pages = 1733–41 | date = June 1999 | pmid = 10318765 | doi =  }}</ref><ref name="pmid21118230">{{cite journal | vauthors = Kaufmann R, Müller P, Hildenbrand G, Hausmann M, Cremer C | title = Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy | journal = Journal of Microscopy | volume = 242 | issue = 1 | pages = 46–54 | date = April 2011 | pmid = 21118230 | doi = 10.1111/j.1365-2818.2010.03436.x }}</ref>
 
Recent evidence has implicated HER2 signaling in resistance to the [[Epidermal growth factor receptor|EGFR]]-targeted cancer drug [[cetuximab]].<ref name="YonesakaZejnullahu2011">{{cite journal | vauthors = 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 | display-authors = 6 | title = Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab | journal = Science Translational Medicine | volume = 3 | issue = 99 | pages = 99ra86 | date = September 2011 | pmid = 21900593 | pmc = 3268675 | doi = 10.1126/scitranslmed.3002442 }}</ref>
 
===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 tumours and some of these tumours 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 dimerisation of this protein in the absence of a ligand.<ref>{{cite journal | vauthors = Brandt-Rauf PW, Rackovsky S, Pincus MR | title = Correlation of the structure of the transmembrane domain of the neu oncogene-encoded p185 protein with its function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 21 | pages = 8660–4 | date = November 1990 | pmid = 1978329 | pmc = 55017 | doi = 10.1073/pnas.87.21.8660 | bibcode = 1990PNAS...87.8660B }}</ref>
 
HER2 mutations have been found in [[non-small-cell lung cancer]]s (NSCLC) and can direct treatment.<ref name="Mazières2013">{{cite journal | vauthors = Mazières J, Peters S, Lepage B, Cortot AB, Barlesi F, Beau-Faller M, Besse B, Blons H, Mansuet-Lupo A, Urban T, Moro-Sibilot D, Dansin E, Chouaid C, Wislez M, Diebold J, Felip E, Rouquette I, Milia JD, Gautschi O | display-authors = 6 | title = Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives | journal = Journal of Clinical Oncology | volume = 31 | issue = 16 | pages = 1997–2003 | date = June 2013 | pmid = 23610105 | doi = 10.1200/JCO.2012.45.6095 }}</ref>
 
==Drugs targeting HER2==
HER2 is the target of the [[monoclonal antibodies|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.<ref name="pmid25848335">{{cite journal | vauthors = Mates M, Fletcher GG, Freedman OC, Eisen A, Gandhi S, Trudeau ME, Dent SF | title = 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 | journal = Current Oncology | volume = 22 | issue = Suppl 1 | pages = S114-22 | date = March 2015 | pmid = 25848335 | pmc = 4381787 | doi = 10.3747/co.22.2322 }}</ref> An important downstream effect of trastuzumab binding to HER2 is an increase in [[CDKN1B|p27]], a protein that halts cell proliferation.<ref name="Le_2005">{{cite journal | vauthors = Le XF, Pruefer F, Bast RC | title = HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways | journal = Cell Cycle | volume = 4 | issue = 1 | pages = 87–95 | date = January 2005 | pmid = 15611642 | doi = 10.4161/cc.4.1.1360 }}</ref> Another monoclonal antibody, [[Pertuzumab]], which inhibits dimerisation of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012.
 
As of November 2015, there are a number of ongoing and recently completed clinical trials of novel targeted agents for HER2+ metastatic breast cancer, e.g. [[margetuximab]].<ref>{{cite journal | vauthors = Jiang H, Rugo HS | title = Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer: how the latest results are improving therapeutic options | journal = Therapeutic Advances in Medical Oncology | volume = 7 | issue = 6 | pages = 321–39 | date = November 2015 | pmid = 26557900 | pmc = 4622301 | doi = 10.1177/1758834015599389 }}</ref>
 
Additionally, [[NeuVax]] ([[Galena Biopharma]]) is a peptide-based immunotherapy that directs "killer" [[T cell]]s 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/mTOR pathway|PI3K/AKT]] molecular pathway.<ref name="pmid19552798">{{cite journal | vauthors = Loi S, Sotiriou C, Haibe-Kains B, Lallemand F, Conus NM, Piccart MJ, Speed TP, McArthur GA | title = Gene expression profiling identifies activated growth factor signaling in poor prognosis (Luminal-B) estrogen receptor positive breast cancer | journal = BMC Medical Genomics | volume = 2 | issue = | pages = 37 | year = 2009 | pmid = 19552798 | pmc = 2706265 | doi = 10.1186/1755-8794-2-37 | laysummary = http://www.sciencedaily.com/releases/2010/05/100506112557.htm | laysource = ScienceDaily }}</ref>
 
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 eostrogen receptors.  Normally, [[estradiol]] and [[tamoxifen]] acting through the eostrogen receptor down-regulate the expression of HER2.  However, when the ratio of the [[coactivator (genetics)|coactivator]] [[nuclear receptor coactivator 3|AIB-3]] exceeds that of the  [[corepressor (genetics)|corepressor]] [[PAX2]], the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant [[breast cancer]].<ref name="urlCORDIS : News">{{cite web | url = http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=30093 | title = Study sheds new light on tamoxifen resistance | authorlink = | date = 2008-11-13 | format = | work = Cordis News | publisher = Cordis | pages = | quote = | accessdate = 2008-11-14}}</ref><ref name="Hurtado1_2008">{{cite journal | vauthors = Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS | title = Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen | journal = Nature | volume = 456 | issue = 7222 | pages = 663–6 | date = December 2008 | pmid = 19005469 | pmc = 2920208 | doi = 10.1038/nature07483 | bibcode = 2008Natur.456..663H }}</ref>
 
[[File:3D Dual Color Super Resolution Microscopy Cremer 2010.png|center|thumb|550px|3D Dual Color Super Resolution Microscopy Cremer 2010.png|Her2 and Her3 distribution on a breast cell, (3D Dual Colour Super Resolution Microscopy SPDMphymod / LIMON, marked with Alexa 488 and 568)]]
{{Clear}}
 
==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.<ref name="pmid17687157">{{cite journal | vauthors = Telli ML, Hunt SA, Carlson RW, Guardino AE | title = Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility | journal = Journal of Clinical Oncology | volume = 25 | issue = 23 | pages = 3525–33 | date = August 2007 | pmid = 17687157 | doi = 10.1200/JCO.2007.11.0106 }}</ref> For HER2-negative tumours, the risks of trastuzumab clearly outweigh the benefits.
 
=== HER2 testing on tumour ===
 
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.{{citation needed|date=June 2016}}
 
=== 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.<ref name="pmid18661530">{{cite journal | vauthors = Ali SM, Carney WP, Esteva FJ, Fornier M, Harris L, Köstler WJ, Lotz JP, Luftner D, Pichon MF, Lipton A | title = Serum HER-2/neu and relative resistance to trastuzumab-based therapy in patients with metastatic breast cancer | journal = Cancer | volume = 113 | issue = 6 | pages = 1294–301 | date = September 2008 | pmid = 18661530 | doi = 10.1002/cncr.23689 }}</ref> However, its ability to determine eligibility for trastuzumab therapy is less clear.<ref name="pmid19255335">{{cite journal | vauthors = Lennon S, Barton C, Banken L, Gianni L, Marty M, Baselga J, Leyland-Jones B | title = Utility of serum HER2 extracellular domain assessment in clinical decision making: pooled analysis of four trials of trastuzumab in metastatic breast cancer | journal = Journal of Clinical Oncology | volume = 27 | issue = 10 | pages = 1685–93 | date = April 2009 | pmid = 19255335 | doi = 10.1200/JCO.2008.16.8351 }}</ref>
 
==HER2 interactions==
 
HER2/neu has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[Beta-catenin|CTNNB1]],<ref name = pmid11950845>{{cite journal | vauthors = Schroeder JA, Adriance MC, McConnell EJ, Thompson MC, Pockaj B, Gendler SJ | title = 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 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 25 | pages = 22692–8 | date = June 2002 | pmid = 11950845 | doi = 10.1074/jbc.M201975200 }}</ref><ref name = pmid11245482>{{cite journal | vauthors = Bonvini P, An WG, Rosolen A, Nguyen P, Trepel J, Garcia de Herreros A, Dunach M, Neckers LM | title = Geldanamycin abrogates ErbB2 association with proteasome-resistant beta-catenin in melanoma cells, increases beta-catenin-E-cadherin association, and decreases beta-catenin-sensitive transcription | journal = Cancer Research | volume = 61 | issue = 4 | pages = 1671–7 | date = February 2001 | pmid = 11245482 | doi =  }}</ref><ref name = pmid7702605>{{cite journal | vauthors = Kanai Y, Ochiai A, Shibata T, Oyama T, Ushijima S, Akimoto S, Hirohashi S | title = c-erbB-2 gene product directly associates with beta-catenin and plakoglobin | journal = Biochemical and Biophysical Research Communications | volume = 208 | issue = 3 | pages = 1067–72 | date = March 1995 | pmid = 7702605 | doi = 10.1006/bbrc.1995.1443 }}</ref>
* [[DLG4]],<ref name = pmid10839362>{{cite journal | vauthors = Huang YZ, Won S, Ali DW, Wang Q, Tanowitz M, Du QS, Pelkey KA, Yang DJ, Xiong WC, Salter MW, Mei L | title = Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses | journal = Neuron | volume = 26 | issue = 2 | pages = 443–55 | date = May 2000 | pmid = 10839362 | doi = 10.1016/s0896-6273(00)81176-9 }}</ref>
* [[Erbin (protein)|Erbin]],<ref name = pmid11278603>{{cite journal | vauthors = Jaulin-Bastard F, Saito H, Le Bivic A, Ollendorff V, Marchetto S, Birnbaum D, Borg JP | title = The ERBB2/HER2 receptor differentially interacts with ERBIN and PICK1 PSD-95/DLG/ZO-1 domain proteins | journal = The Journal of Biological Chemistry | volume = 276 | issue = 18 | pages = 15256–63 | date = May 2001 | pmid = 11278603 | doi = 10.1074/jbc.M010032200 }}</ref><ref name = pmid10878805>{{cite journal | vauthors = 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 | title = Collective nomenclature for LAP proteins | journal = Nature Cell Biology | volume = 2 | issue = 7 | pages = E114 | date = July 2000 | pmid =  10878817| doi = 10.1038/35017119 }}</ref><ref name = pmid12379659>{{cite journal | vauthors = Huang YZ, Zang M, Xiong WC, Luo Z, Mei L | title = Erbin suppresses the MAP kinase pathway | journal = The Journal of Biological Chemistry | volume = 278 | issue = 2 | pages = 1108–14 | date = January 2003 | pmid = 12379659 | doi = 10.1074/jbc.M205413200 }}</ref>
* [[GRB2]],<ref name = pmid16729043>{{cite journal | vauthors = Schulze WX, Deng L, Mann M | title = Phosphotyrosine interactome of the ErbB-receptor kinase family | journal = Molecular Systems Biology | volume = 1 | issue =  | pages = 2005.0008 | year = 2005 | pmid = 16729043 | pmc = 1681463 | doi = 10.1038/msb4100012 }}</ref><ref name = pmid11606575>{{cite journal | vauthors = Bourguignon LY, Zhu H, Zhou B, Diedrich F, Singleton PA, Hung MC | title = Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185(HER2) and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth | journal = The Journal of Biological Chemistry | volume = 276 | issue = 52 | pages = 48679–92 | date = December 2001 | pmid = 11606575 | doi = 10.1074/jbc.M106759200 }}</ref><ref name = pmid9710588>{{cite journal | vauthors = Olayioye MA, Graus-Porta D, Beerli RR, Rohrer J, Gay B, Hynes NE | title = ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner | journal = Molecular and Cellular Biology | volume = 18 | issue = 9 | pages = 5042–51 | date = September 1998 | pmid = 9710588 | pmc = 109089 | doi = 10.1128/mcb.18.9.5042 }}</ref>
* [[Heat shock protein 90kDa alpha (cytosolic), member A1|HSP90AA1]],<ref name = pmid11071886>{{cite journal | vauthors = Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M, Yarden Y, Neckers L | title = Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90 | journal = The Journal of Biological Chemistry | volume = 276 | issue = 5 | pages = 3702–8 | date = February 2001 | pmid = 11071886 | doi = 10.1074/jbc.M006864200 }}</ref><ref name = pmid18655187>{{cite journal | vauthors = Jeong JH, An JY, Kwon YT, Li LY, Lee YJ | title = Quercetin-induced ubiquitination and down-regulation of Her-2/neu | journal = Journal of Cellular Biochemistry | volume = 105 | issue = 2 | pages = 585–95 | date = October 2008 | pmid = 18655187 | pmc = 2575035 | doi = 10.1002/jcb.21859 }}</ref>
* [[Glycoprotein 130|IL6ST]],<ref name = pmid11821958>{{cite journal | vauthors = Grant SL, Hammacher A, Douglas AM, Goss GA, Mansfield RK, Heath JK, Begley CG | title = An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells | journal = Oncogene | volume = 21 | issue = 3 | pages = 460–74 | date = January 2002 | pmid = 11821958 | doi = 10.1038/sj.onc.1205100 }}</ref>
* [[MUC1]],<ref name = pmid12939402>{{cite journal | vauthors = Li Y, Yu WH, Ren J, Chen W, Huang L, Kharbanda S, Loda M, Kufe D | title = Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein | journal = Molecular Cancer Research | volume = 1 | issue = 10 | pages = 765–75 | date = August 2003 | pmid = 12939402 | doi =  }}</ref><ref name = pmid11278868>{{cite journal | vauthors = Schroeder JA, Thompson MC, Gardner MM, Gendler SJ | title = Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland | journal = The Journal of Biological Chemistry | volume = 276 | issue = 16 | pages = 13057–64 | date = April 2001 | pmid = 11278868 | doi = 10.1074/jbc.M011248200 }}</ref>
* [[PICK1]]<ref name = pmid11278603/> and
* [[PIK3R2]],<ref name = pmid1334406>{{cite journal | vauthors = Gout I, Dhand R, Panayotou G, Fry MJ, Hiles I, Otsu M, Waterfield MD | title = 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 | journal = The Biochemical Journal | volume = 288 | issue = 2 | pages = 395–405 | date = December 1992 | pmid = 1334406 | pmc = 1132024 | doi = 10.1042/bj2880395 }}</ref>
* [[PLCG1]],<ref name = pmid1676673>{{cite journal | vauthors = Peles E, Levy RB, Or E, Ullrich A, Yarden Y | title = Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma | journal = The EMBO Journal | volume = 10 | issue = 8 | pages = 2077–86 | date = August 1991 | pmid = 1676673 | pmc = 452891 | doi =  }}</ref><ref name = pmid1683701>{{cite journal | vauthors = Arteaga CL, Johnson MD, Todderud G, Coffey RJ, Carpenter G, Page DL | title = Elevated content of the tyrosine kinase substrate phospholipase C-gamma 1 in primary human breast carcinomas | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 23 | pages = 10435–9 | date = December 1991 | pmid = 1683701 | pmc = 52943 | doi = 10.1073/pnas.88.23.10435 | bibcode = 1991PNAS...8810435A }}</ref>  and
* [[SHC1]].<ref name = pmid16729043/><ref name = pmid9710588/><ref name = pmid10085134>{{cite journal | vauthors = Wong L, Deb TB, Thompson SA, Wells A, Johnson GR | title = A differential requirement for the COOH-terminal region of the epidermal growth factor (EGF) receptor in amphiregulin and EGF mitogenic signaling | journal = The Journal of Biological Chemistry | volume = 274 | issue = 13 | pages = 8900–9 | date = March 1999 | pmid = 10085134 | doi = 10.1074/jbc.274.13.8900 }}</ref>
{{Div col end}}
 
== See also ==
* [[Ann Marie Rogers]], campaigned for UK NHS to provide Herceptin <!-- only need on the Herceptin page ?? -->
* [[SkBr3|SkBr3 Cell Line]], over-expresses HER2


== References ==
== References ==
{{reflist|2}}
{{reflist|33em}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin|33em}}
{{PBB_Further_reading
* {{cite journal | vauthors = Ross JS, Fletcher JA, Linette GP, Stec J, Clark E, Ayers M, Symmans WF, Pusztai L, Bloom KJ | title = The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy | journal = The Oncologist | volume = 8 | issue = 4 | pages = 307–25 | year = 2003 | pmid = 12897328 | doi = 10.1634/theoncologist.8-4-307 }}
| citations =
* {{cite journal | vauthors = Zhou BP, Hung MC | title = Dysregulation of cellular signaling by HER2/neu in breast cancer | journal = Seminars in Oncology | volume = 30 | issue = 5 Suppl 16 | pages = 38–48 | date = October 2003 | pmid = 14613025 | doi = 10.1053/j.seminoncol.2003.08.006 }}
*{{cite journal | author=Ross JS, Fletcher JA, Linette GP, ''et al.'' |title=The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. |journal=Oncologist |volume=8 |issue= 4 |pages= 307-25 |year= 2003 |pmid= 12897328 |doi= }}
* {{cite journal | vauthors = Ménard S, Casalini P, Campiglio M, Pupa SM, Tagliabue E | title = Role of HER2/neu in tumor progression and therapy | journal = Cellular and Molecular Life Sciences | volume = 61 | issue = 23 | pages = 2965–78 | date = December 2004 | pmid = 15583858 | doi = 10.1007/s00018-004-4277-7 }}
*{{cite journal | author=Zhou BP, Hung MC |title=Dysregulation of cellular signaling by HER2/neu in breast cancer. |journal=Semin. Oncol. |volume=30 |issue= 5 Suppl 16 |pages= 38-48 |year= 2003 |pmid= 14613025 |doi= }}
* {{cite journal | vauthors = Becker JC, Muller-Tidow C, Serve H, Domschke W, Pohle T | title = Role of receptor tyrosine kinases in gastric cancer: new targets for a selective therapy | journal = World Journal of Gastroenterology | volume = 12 | issue = 21 | pages = 3297–305 | date = June 2006 | pmid = 16733844 | pmc = 4087885 | doi = 10.3748/wjg.v12.i21.3297 }}
*{{cite journal | author=Ménard S, Casalini P, Campiglio M, ''et al.'' |title=Role of HER2/neu in tumor progression and therapy. |journal=Cell. Mol. Life Sci. |volume=61 |issue= 23 |pages= 2965-78 |year= 2005 |pmid= 15583858 |doi= 10.1007/s00018-004-4277-7 }}
* {{cite journal | vauthors = Laudadio J, Quigley DI, Tubbs R, Wolff DJ | title = HER2 testing: a review of detection methodologies and their clinical performance | journal = Expert Review of Molecular Diagnostics | volume = 7 | issue = 1 | pages = 53–64 | date = January 2007 | pmid = 17187484 | doi = 10.1586/14737159.7.1.53 }}
*{{cite journal | author=Becker JC, Muller-Tidow C, Serve H, ''et al.'' |title=Role of receptor tyrosine kinases in gastric cancer: new targets for a selective therapy. |journal=World J. Gastroenterol. |volume=12 |issue= 21 |pages= 3297-305 |year= 2006 |pmid= 16733844 |doi= }}
* {{cite journal | vauthors = Bianchi F, Tagliabue E, Ménard S, Campiglio M | title = Fhit expression protects against HER2-driven breast tumor development: unraveling the molecular interconnections | journal = Cell Cycle | volume = 6 | issue = 6 | pages = 643–6 | date = March 2007 | pmid = 17374991 | doi = 10.4161/cc.6.6.4033 }}
*{{cite journal | author=Laudadio J, Quigley DI, Tubbs R, Wolff DJ |title=HER2 testing: a review of detection methodologies and their clinical performance. |journal=Expert Rev. Mol. Diagn. |volume=7 |issue= 1 |pages= 53-64 |year= 2007 |pmid= 17187484 |doi= 10.1586/14737159.7.1.53 }}
*{{cite journal | author=Bianchi F, Tagliabue E, Ménard S, Campiglio M |title=Fhit expression protects against HER2-driven breast tumor development: unraveling the molecular interconnections. |journal=Cell Cycle |volume=6 |issue= 6 |pages= 643-6 |year= 2007 |pmid= 17374991 |doi= }}
}}
{{refend}}
{{refend}}


==Resources==
== External links ==
* [http://www.aacr.org/home/public--media/for-the-media/fact-sheets/cancer-concepts/her2.aspx AACR Cancer Concepts Factsheet on HER2]
* [http://medisapiens.com/ERBB2 ERBB2 expression across human cancerous and healthy tissues]{{dead link|date=October 2017 |bot=InternetArchiveBot |fix-attempted=yes }}
* [http://logikbase.com/website/techprofile.cfm?licid=1027 Her2/neu Vaccine Protects Against Tumor Growth ]
* [https://web.archive.org/web/20080516045758/http://www.aacr.org/home/public--media/for-the-media/fact-sheets/cancer-concepts/her2.aspx AACR Cancer Concepts Factsheet on HER2]
* [http://logikbase.com/website/techprofile.cfm?licid=618 Chimeric molecules and Methods of Use]
* [https://web.archive.org/web/20081011055216/http://www.her2.co.za/care/ Breast Friends for Life Network - A South African Breast Cancer Support Forum for HER2 Positive Women]
* [http://crdd.osdd.net/raghava/herceptinr/ HerceptinR] : Herceptin Resistance Database for Understanding Mechanism of Resistance in Breast Cancer Patients. [http://www.nature.com/srep/2014/140327/srep04483/full/srep04483.html Sci. Rep.] 4:4483
* {{MeshName|Receptor,+erbB-2}}
* {{MeshName|Receptor,+erbB-2}}


 
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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. It is also frequently called HER2 (from human epidermal growth factor receptor 2) or HER2/neu.[1][2][3]

HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Amplification or over-expression 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.[4]

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.[5]

Gene

ERBB2, a known proto-oncogene, is located at the long arm of human chromosome 17 (17q12).

Function

The ErbB family consists of four plasma membrane-bound receptor tyrosine kinases. One of which is erbB-2, and 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. Notably, no ligands for HER2 have yet been identified.[6][7] HER2 can heterodimerise with any of the other three receptors and is considered to be the preferred dimerisation partner of the other ErbB receptors.[8]

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:[9]

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, also known as the over-expression of the ERBB2 gene, occurs in approximately 15-30% of breast cancers.[4][10] It is strongly associated with increased disease recurrence and a poor prognosis.[11] Over-expression is also known to occur in ovarian,[12] stomach, adenocarcinoma of the lung[13] and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma,[14][15] e.g. HER-2 is over-expressed in approximately 7-34% of patients with gastric cancer[16][17] and in 30% of salivary duct carcinomas.[18]

HER2 is co-localised, and, most of the time, co-amplified with the gene GRB7, which is a proto-oncogene associated with breast, testicular germ cell, gastric, and eosophageal tumours.

HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.[19][20]

Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.[21]

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 tumours and some of these tumours 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 dimerisation of this protein in the absence of a ligand.[22]

HER2 mutations have been found in non-small-cell lung cancers (NSCLC) and can direct treatment.[23]

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.[24] An important downstream effect of trastuzumab binding to HER2 is an increase in p27, a protein that halts cell proliferation.[25] Another monoclonal antibody, Pertuzumab, which inhibits dimerisation of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012.

As of November 2015, there are a number of ongoing and recently completed clinical trials of novel targeted agents for HER2+ metastatic breast cancer, e.g. margetuximab.[26]

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.[27]

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 eostrogen receptors. Normally, estradiol and tamoxifen acting through the eostrogen 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.[28][29]

File:3D Dual Color Super Resolution Microscopy Cremer 2010.png
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.[30] For HER2-negative tumours, the risks of trastuzumab clearly outweigh the benefits.

HER2 testing on tumour

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.[citation needed]

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.[31] However, its ability to determine eligibility for trastuzumab therapy is less clear.[32]

HER2 interactions

HER2/neu has been shown to interact with:

See also

References

  1. ↑ "ERBB2 erb-b2 receptor tyrosine kinase 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-06-14.
  2. ↑ Reference, Genetics Home. "ERBB2". Genetics Home Reference. Retrieved 2016-06-19.
  3. ↑ Barh D, Gunduz M (2015-01-22). Noninvasive Molecular Markers in Gynecologic Cancers. CRC Press. p. 427. ISBN 9781466569393.
  4. ↑ 4.0 4.1 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.
  5. ↑ 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. Bibcode:1985Sci...230.1132C. doi:10.1126/science.2999974. PMID 2999974.
  6. ↑ Keshamouni VG, Mattingly RR, Reddy KB (June 2002). "Mechanism of 17-beta-estradiol-induced Erk1/2 activation in breast cancer cells. A role for HER2 AND PKC-delta". The Journal of Biological Chemistry. 277 (25): 22558–65. doi:10.1074/jbc.M202351200. PMID 11960991.
  7. ↑ Rusnak DW, Affleck K, Cockerill SG, Stubberfield C, Harris R, Page M, et al. (October 2001). "The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer". Cancer Research. 61 (19): 7196–203. PMID 11585755.
  8. ↑ 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.
  9. ↑ Roy V, Perez EA (November 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.
  10. ↑ Burstein HJ (October 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.
  11. ↑ Tan M, Yu D (2007). "Molecular mechanisms of erbB2-mediated breast cancer chemoresistance". Advances in Experimental Medicine and Biology. Advances in Experimental Medicine and Biology. 608: 119–29. doi:10.1007/978-0-387-74039-3_9. ISBN 978-0-387-74037-9. PMID 17993237.
  12. ↑ Kumar V, Abbas A, Aster J (2013). Robbins basic pathology. Philadelphia: Elsevier/Saunders. p. 697. ISBN 9781437717815.
  13. ↑ Kumar V, Abbas A, Aster J (2013). Robbins basic pathology. Philadelphia: Elsevier/Saunders. p. 179. ISBN 9781437717815.
  14. ↑ Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S (August 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.
  15. ↑ Buza N, Roque DM, Santin AD (March 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ Chiosea SI, Williams L, Griffith CC, Thompson LD, Weinreb I, Bauman JE, Luvison A, Roy S, Seethala RR, Nikiforova MN (June 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.
  19. ↑ 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". Journal of Cell Science. 112 (11): 1733–41. PMID 10318765.
  20. ↑ 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". Journal of Microscopy. 242 (1): 46–54. doi:10.1111/j.1365-2818.2010.03436.x. PMID 21118230.
  21. ↑ Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, et al. (September 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.
  22. ↑ Brandt-Rauf PW, Rackovsky S, Pincus MR (November 1990). "Correlation of the structure of the transmembrane domain of the neu oncogene-encoded p185 protein with its function". Proceedings of the National Academy of Sciences of the United States of America. 87 (21): 8660–4. Bibcode:1990PNAS...87.8660B. doi:10.1073/pnas.87.21.8660. PMC 55017. PMID 1978329.
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