ERBB2

S Wikipedije, slobodne enciklopedije
ERBB2
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1MFG, 1MFL, 1MW4, 1N8Z, 1QR1, 1S78, 2A91, 2JWA, 2KS1, 2L4K, 3BE1, 3H3B, 3N85, 3PP0, 3RCD, 3MZW, 3WLW, 3WSQ, 4GFU, 4HRL, 4HRM, 4HRN, 2N2A

Identifikatori
AliasiERBB2
Vanjski ID-jeviOMIM: 164870 MGI: 95410 HomoloGene: 3273 GeneCards: ERBB2
EC broj2.7.10.1
Lokacija gena (čovjek)
Hromosom 17 (čovjek)
Hrom.Hromosom 17 (čovjek)[1]
Hromosom 17 (čovjek)
Genomska lokacija za ERBB2
Genomska lokacija za ERBB2
Bend17q12Početak39,687,914 bp[1]
Kraj39,730,426 bp[1]
Lokacija gena (miš)
Hromosom 11 (miš)
Hrom.Hromosom 11 (miš)[2]
Hromosom 11 (miš)
Genomska lokacija za ERBB2
Genomska lokacija za ERBB2
Bend11 61.75 cM|11 DPočetak98,303,296 bp[2]
Kraj98,328,542 bp[2]
Obrazac RNK ekspresije


Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija ErbB-3 class receptor binding
transferase activity
nucleotide binding
protein kinase activity
protein dimerization activity
growth factor binding
RNA polymerase I core binding
kinase activity
protein C-terminus binding
GO:0001948, GO:0016582 protein binding
identical protein binding
protein heterodimerization activity
transmembrane receptor protein tyrosine kinase activity
protein tyrosine kinase activity
protein phosphatase binding
ATP binding
transmembrane signaling receptor activity
phosphatidylinositol-4,5-bisphosphate 3-kinase activity
Receptorska tirozin-kinaza
Ćelijska komponenta integral component of membrane
membrana
myelin sheath
receptor complex
Ćelijska membrana
basolateral plasma membrane
apical plasma membrane
perinuklearno područje citoplazme
endosome membrane
GO:0016023 citoplazmatska vezikula
Jedro
citoplazma
citosol
integral component of plasma membrane
basal plasma membrane
Biološki proces positive regulation of protein phosphorylation
peripheral nervous system development
GO:0009373 regulation of transcription, DNA-templated
negative regulation of immature T cell proliferation in thymus
positive regulation of MAP kinase activity
Fosforilacija
transmembrane receptor protein tyrosine kinase signaling pathway
positive regulation of epithelial cell proliferation
cellular response to growth factor stimulus
Zarastanje rana
oligodendrocyte differentiation
regulation of angiogenesis
positive regulation of translation
transcription, DNA-templated
nervous system development
MAPK cascade
protein phosphorylation
heart development
cell surface receptor signaling pathway
GO:0032320, GO:0032321, GO:0032855, GO:0043089, GO:0032854 positive regulation of GTPase activity
positive regulation of cell growth
regulation of microtubule-based process
neuromuscular junction development
regulation of ERK1 and ERK2 cascade
myelination
protein autophosphorylation
phosphatidylinositol 3-kinase signaling
positive regulation of transcription by RNA polymerase I
Ćelijska proliferacija
positive regulation of transcription by RNA polymerase III
motor neuron axon guidance
enzyme linked receptor protein signaling pathway
GO:0072468 Transdukcija signala
positive regulation of cell adhesion
positive regulation of protein targeting to membrane
ERBB2 signaling pathway
phosphatidylinositol phosphate biosynthetic process
GO:1901313 positive regulation of gene expression
peptidyl-tyrosine phosphorylation
regulation of cell motility
cellular response to epidermal growth factor stimulus
GO:0044324, GO:0003256, GO:1901213, GO:0046019, GO:0046020, GO:1900094, GO:0061216, GO:0060994, GO:1902064, GO:0003258, GO:0072212 regulation of transcription by RNA polymerase II
negative regulation of ERBB signaling pathway
positive regulation of protein kinase B signaling
negative regulation of signal transduction
Ćelijska diferencijacija
negative regulation of apoptotic process
positive regulation of ERK1 and ERK2 cascade
GO:0007243 intracellular signal transduction
positive regulation of cell population proliferation
neuron differentiation
positive regulation of MAPK cascade
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)

NM_001005862
NM_001289936
NM_001289937
NM_001289938
NM_004448

NM_001003817
NM_010152

RefSeq (bjelančevina)
NP_001005862
NP_001276865
NP_001276866
NP_001276867
NP_004439

NP_001369711
NP_001369712
NP_001369713
NP_001369714
NP_001369715
NP_001369716
NP_001369717
NP_001369718
NP_001369719
NP_001369720
NP_001369721
NP_001369722
NP_001369723
NP_001369724
NP_001369725
NP_001369726
NP_001369727
NP_001369728
NP_001369729
NP_001369730
NP_001369731
NP_001369732
NP_001369733
NP_001369734
NP_001369735

NP_001003817

Lokacija (UCSC)Chr 17: 39.69 – 39.73 MbChr 11: 98.3 – 98.33 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Receptor tirozin-protein kinaze erbB-2, znan i kao CD340 (klaster diferencijacije 340), proto-onkogene Neu, Erbb2 (glodarski) ili ERBB2 (ljudski), je protein koji je kod ljudi kodiran genom ERBB2. ERBB je skraćeno od eritroblastičnog onkogena B, gena izoliranog iz ptičjeg genoma. Često se naziva i HER2 (od receptor ljudskog epidermnog faktora rasta 2) ili HER2/neu.[5][6][7]

HER2 je član ljudske porodice receptora za epidermni faktor rasta (HER / EGFR / ERBB). Pokazalo se da pojačavanje ili pretjerano eksprimiranje ovog onkogena ima važnu ulogu u razvoju i napredovanju određenih agresivnih vrsta karcinoma dojke. Posljednjih godina protein je postao važan biomarker i cilj terapije za približno 30% pacijenata sa karcinomom dojke.[8]

Gen

ERBB2, poznati proto-onkogen, nalazi se na dugom kraku ljudskog hromosoma 17 (17q12).

Ime[uredi | uredi izvor]

HER2 je tako nazvan jer ima sličnu strukturu kao receptor za ljudski epidermni faktor rasta ili HER1. Neu je nazvan zato što je izveden iz ćelijske linije glodarskog glioblastoma, tipa neuronskog tumora. ErbB-2 imenovan je zbog sličnosti sa ErbB (ptičji eritroblastozni onkogen B), za onkogen koji je kasnije utvrđeno da kodira EGFR. Molekulsko kloniranje gena pokazalo je da su svi HER2, Neu i ErbB-2 kodirani istim ortholozima.[9]

Dužina polipeptidnog lanca je 1.255 aminokiselina, a molekulska težina 137.910 Da.[10]

Aminokiselinska sekvenca[uredi | uredi izvor]

1020304050
MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLY
QGCQVVQGNLELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLR
IVRGTQLFEDNYALAVLDNGDPLNNTTPVTGASPGGLRELQLRSLTEILK
GGVLIQRNPQLCYQDTILWKDIFHKNNQLALTLIDTNRSRACHPCSPMCK
GSRCWGESSEDCQSLTRTVCAGGCARCKGPLPTDCCHEQCAAGCTGPKHS
DCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACP
YNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHL
REVRAVTSANIQEFAGCKKIFGSLAFLPESFDGDPASNTAPLQPEQLQVF
ETLEEITGYLYISAWPDSLPDLSVFQNLQVIRGRILHNGAYSLTLQGLGI
SWLGLRSLRELGSGLALIHHNTHLCFVHTVPWDQLFRNPHQALLHTANRP
EDECVGEGLACHQLCARGHCWGPGPTQCVNCSQFLRGQECVEECRVLQGL
PREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARC
PSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASP
LTSIISAVVGILLVVVLGVVFGILIKRRQQKIRKYTMRRLLQETELVEPL
TPSGAMPNQAQMRILKETELRKVKVLGSGAFGTVYKGIWIPDGENVKIPV
AIKVLRENTSPKANKEILDEAYVMAGVGSPYVSRLLGICLTSTVQLVTQL
MPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLEDVRLVHRDLAARN
VLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFT
HQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTID
VYMIMVKCWMIDSECRPRFRELVSEFSRMARDPQRFVVIQNEDLGPASPL
DSTFYRSLLEDDDMGDLVDAEEYLVPQQGFFCPDPAPGAGGMVHHRHRSS
STRSGGGDLTLGLEPSEEEAPRSPLAPSEGAGSDVFDGDLGMGAAKGLQS
LPTHDPSPLQRYSEDPTVPLPSETDGYVAPLTCSPQPEYVNQPDVRPQPP
SPREGPLPAARPAGATLERPKTLSPGKNGVVKDVFAFGGAVENPEYLTPQ
GGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEYLG
LDVPV
Simboli

Funkcija[uredi | uredi izvor]

Porodica ErbB sastoji se od četiri plazmamembranske vezana receptora tirozin-kinaza. Jedan od njih je erbB-2, a drugi članovi su receptori za epidermni faktor rasta, erbB-3 (vezanje neuregulina; nedostaje kinazni domen) i erbB-4. Sva četiri sadrže po domen koji važi kao vanćelijski ligand, transmembranski i unutarćelijski domen, koji mogu komunicirati s mnoštvom signalnih molekula i ispoljavati aktivnost koja ovisi o ligandu i neovisno o ligandu. Značajno je da još nisu identificirani ligandi za HER2.[11][12] HER2 može heterodimerizovati sa bilo kojim od preostala tri receptora i smatra se preferiranim partnerom za dimerizaciju ostalih ErbB receptora.[13]

Dimerizacija rezultira autofosforilacijom ostataka tirozina unutar citoplazmatskog domena receptora i pokreće različite signalne puteve.

Transdukcija signala[uredi | uredi izvor]

Signalni putevi koje aktivira HER2 uključuju:[14]

Ukratko, signalizacija putem porodice receptora ErbB pospješuje ćelijsku proliferaciju i suprotstavlja se apoptozama, te stoga mora biti strogo regulirana, kako bi se spriječio nekontrolirani rast ćelija.

Klinički značaj[uredi | uredi izvor]

Rak[uredi | uredi izvor]

Amplifikacija, poznata i kao pretjerana ekspresija gena ERBB2, javlja se u približno 15-30% karcinoma dojke.[8][15] Snažno je povezana sa povećanim ponavljanjem bolesti i lošom prognozom; međutim, agensi s lijekovima koji ciljaju HER2 u raku dojke značajno su pozitivno promijenili inače lošu prognozu prirodne historije HER2 pozitivnog karcinoma dojke.[16] Također je poznato da se prekomjerna ekspresija javlja i jajnicima,[17] stomaku, adenokarcinomu pluća[18] i agresivnim oblicima karcinoma maternice, kao što je maternični serozni karcinom endometrija,[19][20] npr. HER2 je prekomjerno eksprimiran kod približno 7-34% pacijenata sa karcinomom želuca [21][22] i kod 30% karcinoma pljuvačnih kanala.[23]

HER2 je kolokaliziran i većinu vremena se pojačava s genom GRB7, koji je proto-onkogen povezan s tumorima dojke, zametnih ćelija testisa, želuca i jednjaka.

Pokazalo se da proteini HER2 formiraju nakupine u ćelijskim membranama koje mogu imati ulogu u tumorigenezi.[24][25]

Dokazi su takođe implicirali signalizaciju HER2 u otpornosti na EGFR-ciljani lijek protiv raka, cetuksimab.[26]

Mutacije[uredi | uredi izvor]

Identificirane su različite strukturne promjene koje uzrokuju mutiranje ovog receptora neovisno o ligandu, i to u odsustvu pretjerane ekspresije receptora. HER2 se nalazi u raznim tumorima, a neki od tih tumora nose točkaste mutacije u nizu koji određuje transmembranski domen HER2. Zamjena valina glutaminskom kiselinom u transmembranskom domenu može rezultirati konstitutivnom dimerizacijom ovog proteina u odsustvu liganda.[27]

Mutacije HER2 pronađene su u raku pluća ne-malih ćelija (NSCLC) i mogu usmjeriti liječenje.[28]

Kao meta lijekova[uredi | uredi izvor]

HER2 je meta monoklonskih antitijela trastuzumab (u prodaji kao Herceptin). Trastuzumab je efikasan samo kod karcinoma kod kojih je HER2 prekomjerno eksprimiran. Jednogodišnja terapija trastuzumabom preporučuje se svim pacijentima sa HER2 pozitivnim karcinomom dojke koji također primaju hemoterapiju.[29] Dvanaest mjeseci terapije trastuzumabom je optimalno. Randomizirana ispitivanja nisu pokazala dodatnu korist nakon 12 mjeseci, dok se pokazalo da je šest mjeseci inferiorno u odnosu na 12. Trastuzumab se daje intravenozno sedmično ili svake tri sedmice.[30]

Važan nizvodni učinak vezanja trastuzumaba za HER2 je povećanjep27, proteina koji zaustavlja proliferaciju ćelija.[31] FDA je odobrila za upotrebu u kombinaciji sa trastuzumabom u junu 2012. godine još jedno monoklonsko antitelo, Pertuzumab, koje inhibira dimerizaciju HER2 i HER3 receptora.

Od novembra 2015. postoji niz tekućih i nedavno završenih kliničkih ispitivanja novih ciljanih sredstava za HER2 + metastatski rak dojke, npr. margetuximab.[32]

Pored toga, NeuVax (marka Galena Biopharma) je imunoterapija zasnovana na peptidu, koja usmjerava T-ćelije "ubice" na ciljanje i uništavanje ćelija karcinoma koje eksprimiraju HER2. Ušao je u fazu 3 kliničkih ispitivanja.

Utvrđeno je da pacijenti sa ER + (estrogenski receptor pozitivan) / HER2 + u poređenju sa ER-/ HER2 + karcinomom dojke zapravo mogu imati veću korist od lijekova koji inhibirajuPI3K / AKT molekulski put.[33]

Prekomjerna ekspresija HER2 također se može suzbiti pojačavanjem drugih gena. Sada se provodi istraživanje kako bi se otkrilo koji geni mogu imati ovaj željeni efekat.

Ekspresija HER2 regulira se signaliziranjem putem estrogenskih receptora. Uobičajeno, estradiol i tamoksifen, koji deluju preko estrogenskog receptora reguliraju ekspresiju HER2. Međutim, kada odnoskoaktivator< AIB-3 premaši odnos korepresor PAX2, ekspresija HER2 povećana je u prisustvu tamoksifena, što dovodi do rezistencije raka dojke na tamoksifen.[34][35]

Distribucija Her2 i Her3 na ćelijama dojke (3D dvojna mikroskopska superrezolucija u boji SPDMphymod/LIMON, označeno programom Alexa 488 i 568)

Dijagnostika[uredi | uredi izvor]

Biopsija raka[uredi | uredi izvor]

Ispitivanje HER2 vrši se kod pacijenata sa rakom dojke radi procjene prognoze i utvrđivanja pogodnosti za terapiju trastuzumabom. Važno je da je trastuzumab ograničen na HER2 pozitivne osobe jer je skup i povezan je sa toksičnošću za srce.[36] Za HER2 pozitivne tumore, rizici trastuzumaba očito premašuju koristi.

Bojenje Her 2 u tkivu karcinoma dojke identificirano kao stadij 3
Bojenjem se vidi ćelijska membrana kontinuirane smeđe boje.

Testovi se obično izvode na uzorcima biopsija dojke, dobijenih bilo putem aspiracija tanke igle, biopsijom jezgrene igle, biopsijom dojke uz pomoć vakuuma ili hirurškim izrezivanjem. Imunohistohemijski metodi koriste se za mjerenje količine HER2 proteina prisutnog u uzorku. Primjeri ovog ispitivanja uključuju HercepTest, Dako, Glostrup i Danmark. Uzorak se ocjenjuje na osnovu uzorka bojenja ćelijske membrane.

Imunohistohemija
Rezultat[37][38] Status[37][38] Svojstvo
0 Negativni HER2
(Nema)
Negativna ekspresija proteina HER2 [39]
1+ Slabo ili nepotpuno bojenje membrane u bilo kojim ćelijama tumora.[39]
2+ Granično/nedvosmisleno
  • Potpuno bojenje membrane koje je ili neujednačenog ili slabog intenziteta, ali ima obodnu distribuciju u najmanje 10% ćelija.[38][39]

ili ujednačeno intenzivno bojenje membrane na 30% ili manje tumorskih ćelija.[39]

3+ Pozitivan HER2 Ujednačeno intenzivno bojenje membrane na 30% ili manje tumorskih ćelija.[38][39]

Uzorci s dvosmislenim IHC rezultatima bi potom trebali biti potvrđeni upotrebom fluorescentnom in situ hibridizacijom (FISH). FISH se može koristiti za mjerenje broja prisutnih kopija gena i smatra se pouzdanijim od IHC.[40]

Serum[uredi | uredi izvor]

Vanćelijski domen HER2 može se izbaciti s površine tumorskih ćelija i ući u cirkulaciju. Mjerenje serumskog HER2 enzimski povezanim imunosorbentskim testom (ELISA) nudi daleko manje invazivnu metodu određivanja HER2 statusa od biopsije i stoga je opsežno istraženo. Dosadašnji rezultati sugeriraju da bi promjene u koncentraciji HER2 u serumu mogle biti korisne u predviđanju odgovora na terapiju trastuzumabom.[41] However, its ability to determine eligibility for trastuzumab therapy is less clear.[42]

Interakcije[uredi | uredi izvor]

Dokazano je da HER2 / neu ima interakcije sa:

See also[uredi | uredi izvor]

Reference[uredi | uredi izvor]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000141736 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000062312 - Ensembl, maj 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "ERBB2 erb-b2 receptor tyrosine kinase 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Pristupljeno 14. 6. 2016.
  6. ^ "ERBB2". Genetics Home Reference. Pristupljeno 19. 6. 2016.
  7. ^ Barh D, Gunduz M (22. 1. 2015). Noninvasive Molecular Markers in Gynecologic Cancers. CRC Press. str. 427. ISBN 9781466569393.
  8. ^ a b 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.
  9. ^ Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U (decembar 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.
  10. ^ "UniProt, P04626". Pristupljeno 22. 6. 2021.
  11. ^ Keshamouni VG, Mattingly RR, Reddy KB (juni 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.
  12. ^ Rusnak DW, Affleck K, Cockerill SG, Stubberfield C, Harris R, Page M, et al. (oktobar 2001). "The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer". Cancer Research. 61 (19): 7196–203. PMID 11585755.
  13. ^ 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.
  14. ^ Roy V, Perez EA (novembar 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.
  15. ^ Burstein HJ (oktobar 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. S2CID 26675265.
  16. ^ Tan M, Yu D (2007). "Molecular mechanisms of erbB2-mediated breast cancer chemoresistance". Breast Cancer Chemosensitivity. Advances in Experimental Medicine and Biology. 608. str. 119–29. doi:10.1007/978-0-387-74039-3_9. ISBN 978-0-387-74037-9. PMID 17993237.
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  19. ^ 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. S2CID 25674060.
  20. ^ Buza N, Roque DM, Santin AD (mart 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.
  21. ^ Rüschoff J, Hanna W, Bilous M, Hofmann M, Osamura RY, Penault-Llorca F, van de Vijver M, Viale G (maj 2012). "HER2 testing in gastric cancer: a practical approach". Modern Pathology. 25 (5): 637–50. doi:10.1038/modpathol.2011.198. PMID 22222640.
  22. ^ 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.
  23. ^ Chiosea SI, Williams L, Griffith CC, Thompson LD, Weinreb I, Bauman JE, Luvison A, Roy S, Seethala RR, Nikiforova MN (juni 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. S2CID 34106002.
  24. ^ Nagy P, Jenei A, Kirsch AK, Szöllosi J, Damjanovich S, Jovin TM (juni 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.
  25. ^ 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. S2CID 2119158.
  26. ^ Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, et al. (septembar 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.
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