Wikipedia

C-jun

c-Jun jest protein koji je kod ljudi kodiran genom JUN sa hromosoma 1. c-Jun, u kombinaciji sa c-Fos, formira AP-1 transkripcijski faktor za rani odgovor, Prvo je identificiran kao Fos-vezujući protein p39 i tek kasnije ponovo otkriven kao proizvod gena JUN. c-jun je bio prvootkriveni onkogeni transkripcijski faktor.[5] The proto-oncogene c-Jun je ćelijski homolog virusnog onkoproteina v-jun (P05411).[6] Virusni homolog v-jun je otkriven u virusu 17ptičjeg sarkoma i dobio je ime po ju-nana, japanski riječ za 17.[7] Ljudski JUN kodira protein veoma sličan virusnom proteinu, koji direktno stupa u interakciju sa specifičnim ciljnim sekvencama DNK, kako bi regulirao ekspresiju gena. Ovaj gen je bez introna i mapiran je na 1p32-p31, hromozomsku regiju koja je uključena u translokacije i delecije kod ljudskih malignosti.[8]

JUN
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1A02, 1JNM, 1JUN, 1S9K, 1T2K, 1FOS

Identifikatori
AliasiJUN
Vanjski ID-jeviOMIM: 165160 MGI: 96646 HomoloGene: 1679 GeneCards: JUN
Lokacija gena (čovjek)
Hromosom 1 (čovjek)
Hrom.Hromosom 1 (čovjek)[1]
Hromosom 1 (čovjek)
Genomska lokacija za JUN
Genomska lokacija za JUN
Bend1p32.1Početak58,776,845 bp[1]
Kraj58,784,048 bp[1]
Lokacija gena (miš)
Hromosom 4 (miš)
Hrom.Hromosom 4 (miš)[2]
Hromosom 4 (miš)
Genomska lokacija za JUN
Genomska lokacija za JUN
Bend4 C5|4 43.34 cMPočetak94,937,271 bp[2]
Kraj94,940,459 bp[2]
Obrazac RNK ekspresije




Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija• GO:0005097, GO:0005099, GO:0005100 GTPase activator activity
• GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity
• GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific
• GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific
• cAMP response element binding
• R-SMAD binding
• HMG box domain binding
• transcription factor binding
• GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding
• transcription factor activity, RNA polymerase II core promoter proximal region sequence-specific binding
• vezivanje enzima
• chromatin binding
• GO:0001948, GO:0016582 vezivanje za proteine
• double-stranded DNA binding
• vezivanje sa DNK
• sequence-specific DNA binding
• GO:0001105 transcription coactivator activity
• vezivanje identičnih proteina
• transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding
• vezivanje sa RNK
• protein homodimerization activity
• protein heterodimerization activity
• ubiquitin protein ligase binding
• ubiquitin-like protein ligase binding
• GO:0000975 transcription cis-regulatory region binding
Ćelijska komponenta• citosol
• transcription repressor complex
• jedro
• nuclear chromosome
• nukleoplazma
• transcription regulator complex
• transcription factor AP-1 complex
Biološki proces• GO:1904089 negative regulation of neuron apoptotic process
• negative regulation of DNA binding
• outflow tract morphogenesis
• transcription by RNA polymerase II
• Učenje
• monocyte differentiation
• response to organic substance
• leading edge cell differentiation
• Fc-epsilon receptor signaling pathway
• positive regulation of neuron apoptotic process
• cellular response to hormone stimulus
• regulation of DNA-binding transcription factor activity
• Jednodnevni biološki ritam
• Angiogeneza
• positive regulation of ERK1 and ERK2 cascade
• Ras protein signal transduction
• transforming growth factor beta receptor signaling pathway
• negative regulation of cell population proliferation
• response to muscle stretch
• cellular response to calcium ion
• response to cytokine
• GO:0009373 regulation of transcription, DNA-templated
• SMAD protein signal transduction
• axon regeneration
• positive regulation of fibroblast proliferation
• response to mechanical stimulus
• positive regulation of epithelial cell migration
• positive regulation of DNA-templated transcription, initiation
• transcription, DNA-templated
• positive regulation of cell differentiation
• positive regulation of monocyte differentiation
• positive regulation of pri-miRNA transcription by RNA polymerase II
• negative regulation of protein autophosphorylation
• membrane depolarization
• negative regulation of apoptotic process
• eyelid development in camera-type eye
• microglial cell activation
• positive regulation of DNA replication
• response to lipopolysaccharide
• response to radiation
• response to cAMP
• GO:0045996 negative regulation of transcription, DNA-templated
• response to hydrogen peroxide
• positive regulation of smooth muscle cell proliferation
• positive regulation of endothelial cell proliferation
• GO:1904578 response to organic cyclic compound
• GO:0010260 starenje
• regulation of cell cycle
• regulation of cell population proliferation
• positive regulation of cell population proliferation
• liver development
• negative regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress
• cellular response to potassium ion starvation
• GO:0006928 cellular process or phenomenon
• release of cytochrome c from mitochondria
• GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II
• GO:0032320, GO:0032321, GO:0032855, GO:0043089, GO:0032854 positive regulation of GTPase activity
• GO:0072353 cellular response to reactive oxygen species
• positive regulation of apoptotic process
• GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated
• cellular response to cadmium ion
• GO:1901227 negative regulation of transcription by RNA polymerase II
• positive regulation of vascular associated smooth muscle cell proliferation
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

3725

16476

Ensembl

ENSG00000177606

ENSMUSG00000052684

UniProt

P05412

P05627

RefSeq (mRNK)

NM_002228

NM_010591

RefSeq (bjelančevina)

NP_002219

NP_034721

Lokacija (UCSC)Chr 1: 58.78 – 58.78 MbChr 4: 94.94 – 94.94 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Aminokiselinska sekvenca

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Dužina polipeptidnog lanca je 331 aminokiselina, a molekulska težina 35.676 Da.[9]

1020304050
MTAKMETTFYDDALNASFLPSESGPYGYSNPKILKQSMTLNLADPVGSLK
PHLRAKNSDLLTSPDVGLLKLASPELERLIIQSSNGHITTTPTPTQFLCP
KNVTDEQEGFAEGFVRALAELHSQNTLPSVTSAAQPVNGAGMVAPAVASV
AGGSGSGGFSASLHSEPPVYANLSNFNPGALSSGGGAPSYGAAGLAFPAQ
PQQQQQPPHHLPQQMPVQHPRLQALKEEPQTVPEMPGETPPLSPIDMESQ
ERIKAERKRMRNRIAASKCRKRKLERIARLEEKVKTLKAQNSELASTANM
LREQVAQLKQKVMNHVNSGCQLMLTQQLQTF

Funkcija

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Regulacija

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I Jun i njegovi dimerizacijski partneri u formiranju AP-1 podložni su regulaciji različitim vanćelijskim stimulansima, koji uključuju peptidne faktore rasta, proupalne citokine, oksidativni i druge oblike ćelijskog stresa i UV-zračenje. Naprimjer, UV-zračenje je moćan induktor za povišenu ekspresiju c-juna.[6]

Transkripcija c-juna autoregulirana je sopstvenim proizvodom, Jun. Vezivanje Juna (AP-1) za AP-1 vezu visokog afiniteta u jun promotorskoj regiji indukuje jun transkripciju. Ova pozitivna autoregulacija stimulacijom sopstvene transkripcije može biti mehanizam za produžavanje signala vanćelijskih stimulusa. Ovaj mehanizam može imati biološki značaj za aktivnost c-juna kod raka.[10][11]

Također, aktivnosti c-juna mogu se regulirati putem ERK-a. Utvrđeno je da konstitutivno aktivan ERK povećava transkripciju i stabilnost c-juna preko CREB i GSK3. Ovo rezultira aktiviranim c-jun i njegovim nizvodnim ciljevima kao što su RACK1 i ciklin D1. RACK1 može poboljšati JNK aktivnost, a aktivirana JNK signalizacija naknadno regulira aktivnost c-juna.[12]

Aktivira se dvostrukom fosforilacijom putem JNK puta, ali ima i funkciju neovisnu od fosforilacije. Nokaut c-juna je smrtonosan, ali transgene životinje s mutiranim c-junom koji ne može biti fosforiliran (nazvan c-junAA) mogu preživjeti.

Fosforilacija Juna na serinima 63 i 73 i treoninima 91 i 93 povećava transkripciju c-jun ciljnih gena.[13] Stoga, regulacija aktivnosti c-juna može se postići fosforilacijom na N-terminalnom spoju pomoću Jun N-terminalnih kinaza (JNK). Pokazalo se da je Junova aktivnost (aktivnost AP-1) u apoptozi izazvanoj stresom i ćelijskoj proliferaciji regulirana njegovom N-terminalnom fosforilacijom.[14] Druga studija pokazala je da onkogena transformacija ras i fos također zahtijeva jun N-terminalnu fosforilaciju na serinima 63 i 73.[15]

Progresija ćelijskog ciklusa

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Studije su pokazale da je c-jun neophodan za napredovanje kroz G1-fazu ćelijskog ciklusa, a c-jun nulte ćelije pokazuju povećano zaustavljanje G1. C-jun regulira nivo transkripcije ciklina D, koji je glavna Rb-kinaza. Rb je supresor rasta, a inaktivira se fosforilacijom. Stoga je c-jun neophodan za održavanje dovoljne aktivnosti ciklin D- kinaze i omogućavanje napredovanja ćelijskog ciklusa.[6]

U ćelijama bez c-juna, ekspresija p53 (induktor zaustavljanja ćelijskog ciklusa) i p21 (CDK inhibitor i p53 ciljni gen) je povećana i te ćelije pokazuju defekt ćelijskog ciklusa. Prekomjerna ekspresija c-jun u ćelijama dovodi do sniženog nivoa p53 i p21, te pokazuje ubrzanu proliferaciju ćelija. C-jun potiskuje transkripciju p53, vezivanjem za varijantu AP-1 mjesta u promotoru p53. Ovi rezultati pokazuju da c-jun smanjuje regulaciju p53, kako bi kontrolirao progresiju ćelijskog ciklusa.[16]

Antiapoptozna aktivnost

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UV zračenje može aktivirati ekspresiju c-jun i JNK signalni put. C-jun štiti ćelije od apoptoza izazvanih UV-zračenjem i sarađuje sa NF-κB, kako bi sprečio apoptozu izazvanu putem TNFα. Zaštita od apoptoze pomoću c-juna zahtijeva serine 63/73 (uključene u fosforilaciju Juna), što nije potrebno u napretku G1 posredovanom c-junom. Ovo sugerira da c-jun regulira progresiju ćelijskog ciklusa i apoptozu putem dva odvojena mehanizma.[6]

Studija je koristila jetreno specifičnu inaktivaciju c-juna kod hepatoćelijskog karcinoma, što je pokazalo da je poremećeni razvoj tumora u korelaciji sa povećanim nivoom proteina p53 i nivoom iRNK ciljnog gena p53 PMAIP1. Također, c-jun može zaštititi hepatocite od apoptoze, jer hepatociti nemaju c-jun, pokazuju povećanu osjetljivost na apoptozu izazvanu putem TNFα. U onim hepatocitima kojima nedostaje c-jun, delecija p53 može vratiti otpornost prema TNFα. Ovi rezultati pokazuju da c-jun antagonizira proapoptotsku aktivnost p53 u tumoru jetre.[17]

Klinički značaj

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Poznato je da c-jun ima ulogu u ćelijskoj proliferaciji i apoptozi endometrija tokom menstruacijskog ciklusa. Ciklična promjena nivoa c-jun proteina značajna je u proliferaciji i apoptozi epitelnih ćelija u žlijezdama. Perzistentna stromna ekspresija c-jun proteina može spriječiti stromne ćelije da uđu u apoptozu tokom kasne sekretorne faze.[18]

Kancer

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U studiji koja je koristila nemaloćelijski karcinom pluća (NSCLC), utvrđeno je da je c-jun prekomjerno izražen u 31% slučajeva kod primarnih i metastatskih tumora pluća, dok je normalan provodni disajni put i alveolni epitel općenito nije eksperimirao c-jun.[19]

Studija sa grupom koja se sastojala od 103 slučaja faze I/II invazivnih karcinoma dojke pokazala je da je aktivirani c-jun eksprimiran pretežno na invazivnom prednjem dijelu raka dojke i povezan je sa proliferacijom i angiogenezom.[20]

Inicijacija tumora

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Urađena je studija sa specifičnom inaktivacijom c-juna za jetru, u različitim fazama razvoja tumora kod miševa sa hemijski izazvanim hepatoćelijskim karcinomom. Rezultat ukazuje da je c-jun potreban u ranoj fazi razvoja tumora, a delecija c-juna može u velikoj mjeri potisnuti formiranje tumora. Također, c-jun je neophodan za preživljavanje tumorskih ćelija između faze inicijacije i progresije. Za razliku od toga, inaktivacija c-juna kod uznapredovalih tumora ne ometa progresiju tumora.[17]

Rak dojke

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Prekomjerna ekspresija c-juna u ćelijama MCF-7 može rezultirati ukupnom povećanom agresivnošću, što je prikazano povećanom ćelijskom pokretljivošću, povećanom ekspresijom enzima koji razgrađuje matriks MMP-9, povećanom in vitro hemoinvazijom i formiranjem tumora na golim miševima u odsustvu egzogenih estrogena. Ćelije MCF-7 sa prekomjernom ekspresijom c-jun postale su nereaaktivne na estrogen i tamoksifen, tako da se pretpostavlja da prekomjerna ekspresija c-juna dovodi do fenotipa neovisnog od estrogena u ćelijama raka dojke. Uočeni fenotip za MCF-7 ćelije s prekomjernom ekspresijom c-juna sličan je onom koji je klinički uočen kod uznapredovalog karcinoma dojke, koji nije reagirao na hormone.[21]

Invazivni fenotip kojem doprinosi prekomjerna ekspresija c-juna potvrđen je u drugoj studiji. Osim toga, ova studija pokazala je povećane in vivo metastaza u jetri zbog raka dojke s prekomjernom ekspresijom c-juna. Ovo otkriće sugerira da c-jun ima ključnu ulogu u metastazama raka dojke.[22]

Kod tumora dojke, endogeni c-jun ima ključnu ulogu u ErbB2-indukovanoj migraciji i invaziji epitelnih ćelija dojke. Jun transkripcijski aktivira promotore SCF (faktor matičnih ćelija) i CCL5. Indukovana ekspresija SCF i CCL5 promovira samoobnavljajuću populaciju epitela dojke. To sugerira da c-jun posreduje u ekspanziji matičnih ćelija raka dojke, kako bi se povećala invazivnost tumora.[23]

Kancer vulve

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Uočeno je da je C-jun prekomjerno eksprimiran u uzorcima karcinom pločastih ćelija vulve, u vezi sa inaktivacijom gena za supresiju tumora RARB izazvanom hipermetilacijom.[10] Zaista, viši nivoi iRNK c-Juna testirani su u uzorcima raka vulve u poređenju sa onima normalne kože i preneoplazijskih lezija vulve, čime se naglašava unakrsna veza između RARB gena i onkogena c-Jun.[10]

Ćelijska diferencijacija

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Deset nediferenciranih i visoko agresivnih sarkoma pokazalo je amplifikaciju jun gena i prekomjernu ekspresiju JUN na nivou RNK i proteina. Prekomjerna ekspresija c-jun u ćelijama 3T3-L1 (preadipocitna netumorska ćelijska linija koja podsjeća na ljudski liposarkom) može blokirati ili odgoditi adipocitnu diferencijaciju tih ćelija.[24]

Regeneracija nerava i kičmene moždine

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Povreda perifernih živaca kod glodara brzo aktivira JNK signalizaciju koja zauzvrat aktivira c-Jun. Nasuprot tome, povreda nerava u centralnom nervnom sistemu nema tgakv e posljedice. c-Jun je dovoljan da podstakne regeneraciju aksona i u perifernom i u centralnom nervnom sistemu, jer prekomjerna ekspresija u neuronima ganglija dorzalnog korijena i neuronima kore dovodi do povećane regeneracije.[25]

Kao cilj lijeka protiv raka

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Budući da je c-jun uočen prekomjerno izražen kod raka,[10] nekoliko studija je naglasilo hipotezu da bi ovaj gen mogao biti meta za terapiju raka. Studija je pokazala da onkogena transformacija ras i fos zahtijeva N-terminalnu fosforilaciju jun na serinima 63 i 73 pomoću Jun N-terminalnih kinaza (JNK). U ovoj studiji, inducirani tumor kože i osteosarkom pokazali su poremećen razvoj kod miševa sa mutantnim Jun koji nije sposoban za fosforilaciju N-terminala.[15] Također, u mišjem modelu raka crijeva, genetička abrogacija Jun, N-terminalna fosforilacija ili inaktivacija c-juna specifična za crijeva oslabila je razvoj raka i produžila životni vijek.[13] Stoga ciljanje na fosforilaciju N-terminala Jun (ili JNK signalni put) može biti potencijalna strategija za inhibiciju rasta tumora.

U ćelijama raka B16-F10 dobijenim od melanoma, inaktivacija c-juna farmakološkim JNK/jun inhibitorom SP, u kombinaciji sa obaranjem JunB može dovesti do citotoksičnog efekta, što dovodi do zaustavljanja rasta ćelije i apoptoze. Ova anti-JunB/Jun strategija može povećati preživljavanje miševa inokuliranih tumorskim ćelijama, što sugerira potencijalnu antitumorsku strategiju putem inhibicije Juna i JunB.[26]

Antikancerska svojstva c-jun

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Većina rezultata istraživanja pokazuje da c-jun doprinosi inicijaciji tumora i povećanju invazivnosti. Međutim, nekoliko studija je otkrilo neke alternativne aktivnosti c-juna, sugerirajući da bi c-jun zapravo mogao biti mač sa dvije oštrice kod raka.

p16

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p16INK4a je supresor tumora i inhibitor ćelijskog ciklusa, a studija pokazuje da c-jun djeluje kao “tjelohranitelj” p16INK4a, sprečavajući metilaciju promotora p16INK4a. Stoga, c-jun može spriječiti utišavanje gena p16INK4a.

Tiloforin

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Tiloforin je tip alkaloida biljnog porijekla s antikancerogenim djelovanjem, izazivanjem zaustavljanja ćelijskog ciklusa. Studija je pokazala da tretman tiloforinom povećava akumulaciju c-jun proteina. Zatim ekspresija c-juna u sprezi sa tiloforinom podstiče zaustavljanje G1 u ćelijama karcinoma kroz smanjenje ciklina A2. Stoga, rezultat ukazuje da je antikancerogeni mehanizam tiloforina posredovan c-junom.[27]

Interakcije

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Pokazalo se da je C-jun u interakciji sa:

Također pogledajte

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Reference

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000177606 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000052684 - 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. ^ Vogt PK (juni 2002). "Fortuitous convergences: the beginnings of JUN". Nature Reviews. Cancer. 2 (6): 465–9. doi:10.1038/nrc818. PMID 12189388. S2CID 44145552.
  6. ^ a b c d Wisdom R, Johnson RS, Moore C (januar 1999). "c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms". The EMBO Journal. 18 (1): 188–97. doi:10.1093/emboj/18.1.188. PMC 1171114. PMID 9878062.
  7. ^ Maki Y, Bos TJ, Davis C, Starbuck M, Vogt PK (maj 1987). "Avian sarcoma virus 17 carries the jun oncogene". Proceedings of the National Academy of Sciences of the United States of America. 84 (9): 2848–52. doi:10.1073/pnas.84.9.2848. PMC 304757. PMID 3033666.
  8. ^ "Entrez Gene: JUN jun oncogene".
  9. ^ "UniProt, P05412" (jezik: eng.). Pristupljeno 29. 11. 2021.CS1 održavanje: nepoznati jezik (link)
  10. ^ a b c d Rotondo JC, Borghi A, Selvatici R, Mazzoni E, Bononi I, Corazza M, Kussini J, Montinari E, Gafà R, Tognon M, Martini F (juli 2018). "Association of Retinoic Acid Receptor β Gene With Onset and Progression of Lichen Sclerosus-Associated Vulvar Squamous Cell Carcinoma". JAMA Dermatology. 154 (7): 819–823. doi:10.1001/jamadermatol.2018.1373. PMC 6128494. PMID 29898214.
  11. ^ Angel P, Hattori K, Smeal T, Karin M (decembar 1988). "The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1". Cell. 55 (5): 875–85. doi:10.1016/0092-8674(88)90143-2. PMID 3142689. S2CID 19043736.
  12. ^ Lopez-Bergami P, Huang C, Goydos JS, Yip D, Bar-Eli M, Herlyn M, Smalley KS, Mahale A, Eroshkin A, Aaronson S, Ronai Z (maj 2007). "Rewired ERK-JNK signaling pathways in melanoma". Cancer Cell. 11 (5): 447–60. doi:10.1016/j.ccr.2007.03.009. PMC 1978100. PMID 17482134.
  13. ^ a b Nateri AS, Spencer-Dene B, Behrens A (septembar 2005). "Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development". Nature. 437 (7056): 281–5. Bibcode:2005Natur.437..281N. doi:10.1038/nature03914. PMID 16007074. S2CID 4373376.
  14. ^ Behrens A, Sibilia M, Wagner EF (mart 1999). "Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation". Nature Genetics. 21 (3): 326–9. doi:10.1038/6854. PMID 10080190. S2CID 25622141.
  15. ^ a b Behrens A, Jochum W, Sibilia M, Wagner EF (maj 2000). "Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation". Oncogene. 19 (22): 2657–63. doi:10.1038/sj.onc.1203603. PMID 10851065.
  16. ^ Schreiber M, Kolbus A, Piu F, Szabowski A, Möhle-Steinlein U, Tian J, Karin M, Angel P, Wagner EF (mart 1999). "Control of cell cycle progression by c-Jun is p53 dependent". Genes & Development. 13 (5): 607–19. doi:10.1101/gad.13.5.607. PMC 316508. PMID 10072388.
  17. ^ a b Eferl R, Ricci R, Kenner L, Zenz R, David JP, Rath M, Wagner EF (januar 2003). "Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53". Cell. 112 (2): 181–92. doi:10.1016/S0092-8674(03)00042-4. PMID 12553907. S2CID 8358992.
  18. ^ Udou T, Hachisuga T, Tsujioka H, Kawarabayashi T (2004). "The role of c-jun protein in proliferation and apoptosis of the endometrium throughout the menstrual cycle". Gynecologic and Obstetric Investigation. 57 (3): 121–6. doi:10.1159/000075701. PMID 14691341. S2CID 29512406.
  19. ^ Szabo E, Riffe ME, Steinberg SM, Birrer MJ, Linnoila RI (januar 1996). "Altered cJUN expression: an early event in human lung carcinogenesis". Cancer Research. 56 (2): 305–15. PMID 8542585.
  20. ^ Vleugel MM, Greijer AE, Bos R, van der Wall E, van Diest PJ (juni 2006). "c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer". Human Pathology. 37 (6): 668–74. doi:10.1016/j.humpath.2006.01.022. PMID 16733206.
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