ERBB2
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]10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MELAALCRWG | LLLALLPPGA | ASTQVCTGTD | MKLRLPASPE | THLDMLRHLY | ||||
QGCQVVQGNL | ELTYLPTNAS | LSFLQDIQEV | QGYVLIAHNQ | VRQVPLQRLR | ||||
IVRGTQLFED | NYALAVLDNG | DPLNNTTPVT | GASPGGLREL | QLRSLTEILK | ||||
GGVLIQRNPQ | LCYQDTILWK | DIFHKNNQLA | LTLIDTNRSR | ACHPCSPMCK | ||||
GSRCWGESSE | DCQSLTRTVC | AGGCARCKGP | LPTDCCHEQC | AAGCTGPKHS | ||||
DCLACLHFNH | SGICELHCPA | LVTYNTDTFE | SMPNPEGRYT | FGASCVTACP | ||||
YNYLSTDVGS | CTLVCPLHNQ | EVTAEDGTQR | CEKCSKPCAR | VCYGLGMEHL | ||||
REVRAVTSAN | IQEFAGCKKI | FGSLAFLPES | FDGDPASNTA | PLQPEQLQVF | ||||
ETLEEITGYL | YISAWPDSLP | DLSVFQNLQV | IRGRILHNGA | YSLTLQGLGI | ||||
SWLGLRSLRE | LGSGLALIHH | NTHLCFVHTV | PWDQLFRNPH | QALLHTANRP | ||||
EDECVGEGLA | CHQLCARGHC | WGPGPTQCVN | CSQFLRGQEC | VEECRVLQGL | ||||
PREYVNARHC | LPCHPECQPQ | NGSVTCFGPE | ADQCVACAHY | KDPPFCVARC | ||||
PSGVKPDLSY | MPIWKFPDEE | GACQPCPINC | THSCVDLDDK | GCPAEQRASP | ||||
LTSIISAVVG | ILLVVVLGVV | FGILIKRRQQ | KIRKYTMRRL | LQETELVEPL | ||||
TPSGAMPNQA | QMRILKETEL | RKVKVLGSGA | FGTVYKGIWI | PDGENVKIPV | ||||
AIKVLRENTS | PKANKEILDE | AYVMAGVGSP | YVSRLLGICL | TSTVQLVTQL | ||||
MPYGCLLDHV | RENRGRLGSQ | DLLNWCMQIA | KGMSYLEDVR | LVHRDLAARN | ||||
VLVKSPNHVK | ITDFGLARLL | DIDETEYHAD | GGKVPIKWMA | LESILRRRFT | ||||
HQSDVWSYGV | TVWELMTFGA | KPYDGIPARE | IPDLLEKGER | LPQPPICTID | ||||
VYMIMVKCWM | IDSECRPRFR | ELVSEFSRMA | RDPQRFVVIQ | NEDLGPASPL | ||||
DSTFYRSLLE | DDDMGDLVDA | EEYLVPQQGF | FCPDPAPGAG | GMVHHRHRSS | ||||
STRSGGGDLT | LGLEPSEEEA | PRSPLAPSEG | AGSDVFDGDL | GMGAAKGLQS | ||||
LPTHDPSPLQ | RYSEDPTVPL | PSETDGYVAP | LTCSPQPEYV | NQPDVRPQPP | ||||
SPREGPLPAA | RPAGATLERP | KTLSPGKNGV | VKDVFAFGGA | VENPEYLTPQ | ||||
GGAAPQPHPP | PAFSPAFDNL | YYWDQDPPER | GAPPSTFKGT | PTAENPEYLG | ||||
LDVPV |
- Simboli
C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin
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]
- mitogen-aktivirana protein kinaza (MAPK)
- fosfoinozitid 3-kinaza (PI3K / Akt)
- fosfolipaza C γ
- protein-kinaza C (PKC)
- Pretvarač signala i aktivator transkripcije (STAT).
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]
![](http://178.128.105.246/cars-http-upload.wikimedia.org/wikipedia/commons/thumb/1/1a/3D_Dual_Color_Super_Resolution_Microscopy_Cremer_2010.png/550px-3D_Dual_Color_Super_Resolution_Microscopy_Cremer_2010.png)
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.
![](http://178.128.105.246/cars-http-upload.wikimedia.org/wikipedia/commons/thumb/3/34/Her_2_staining_on_patient_breast_cancer_tissue_identified_as_stage_3.jpg/285px-Her_2_staining_on_patient_breast_cancer_tissue_identified_as_stage_3.jpg)
![](http://178.128.105.246/cars-http-upload.wikimedia.org/wikipedia/commons/thumb/1/1a/Positive_immunohistochemistry_of_HER2_in_invasive_breast_cancer.jpg/285px-Positive_immunohistochemistry_of_HER2_in_invasive_breast_cancer.jpg)
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.
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 |
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]- Ann Marie Rogers, campaigned for UK NHS to provide Herceptin
- SkBr3 Cell Line, over-expresses HER2
Reference
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Dopunska literatura
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Vanjski linkovi
[uredi | uredi izvor]- ERBB2 expression across human cancerous and healthy tissues[trajno mrtav link]
- AACR Cancer Concepts Factsheet on HER2
- Breast Friends for Life Network - A South African Breast Cancer Support Forum for HER2 Positive Women
- HerceptinR : Herceptin Resistance Database for Understanding Mechanism of Resistance in Breast Cancer Patients. Sci. Rep. 4:4483
- Receptor, erbB-2 na US National Library of Medicine Medical Subject Headings (MeSH)
- PDBe-KB provides an overview of all the structure information available in the PDB for Human Receptor tyrosine-protein kinase erbB-2