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Article: ErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells

TitleErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells
Authors
Issue Date2006
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2006, v. 66 n. 4, p. 2028-2037 How to Cite?
AbstractErbB2 overexpression in breast tumors results in increased metastasis and angiogenesis and reduced survival. To study ErbB2 signaling mechanisms in metastasis and angiogenesis, we did a spontaneous metastasis assay using MDA-MB-435 human breast cancer cells stably transfected with constitutively active ErbB2 kinase (V659E), a kinase-dead mutant of ErbB2 (K753M), or vector control (neo). Mice injected with V659E had increased metastasis incidence and tumor microvessel density than mice injected with K753M or control. Increased angiogenesis in vivo from the V659E transfectants paralleled increased angiogenic potential in vitro. V659E produced increased vascular endothelial growth factor (VEGF) through increased VEGF protein synthesis. This was mediated through signaling events involving extracellular signal-regulated kinase, phosphatidylinositol 3-kinase/Akt, mammalian target of rapamycin (mTOR), and p70S6K. The V659E xenografts also had significantly increased phosphorylated Akt, phosphorylated p70S6K, and VEGF compared with controls. To validate the clinical relevance of these findings, we examined 155 human breast tumor samples. Human tumors that overexpressed ErbB2, which have been previously shown to have higher VEGF expression, showed significantly higher p70S6K phosphorylation as well. Increased VEGF expression also significantly correlated with higher levels of Akt and mTOR phosphorylation. Additionally, patients with tumors having increased p70S6K phosphorylation showed a trend for worse disease-free survival and increased metastasis. Our findings show that ErbB2 increases VEGF protein production by activating p70S6K in cell lines, xenografts, and in human cancers and suggest that these signaling molecules may serve as targets for antiangiogenic and antimetastatic therapies. ©2006 American Association for Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/146572
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorKlos, KSen_HK
dc.contributor.authorWyszomierski, SLen_HK
dc.contributor.authorSun, Men_HK
dc.contributor.authorTan, Men_HK
dc.contributor.authorZhou, Xen_HK
dc.contributor.authorLi, Pen_HK
dc.contributor.authorYang, Wen_HK
dc.contributor.authorYin, Gen_HK
dc.contributor.authorHittelman, WNen_HK
dc.contributor.authorYu, Den_HK
dc.date.accessioned2012-05-02T08:37:06Z-
dc.date.available2012-05-02T08:37:06Z-
dc.date.issued2006en_HK
dc.identifier.citationCancer Research, 2006, v. 66 n. 4, p. 2028-2037en_HK
dc.identifier.issn0008-5472en_HK
dc.identifier.urihttp://hdl.handle.net/10722/146572-
dc.description.abstractErbB2 overexpression in breast tumors results in increased metastasis and angiogenesis and reduced survival. To study ErbB2 signaling mechanisms in metastasis and angiogenesis, we did a spontaneous metastasis assay using MDA-MB-435 human breast cancer cells stably transfected with constitutively active ErbB2 kinase (V659E), a kinase-dead mutant of ErbB2 (K753M), or vector control (neo). Mice injected with V659E had increased metastasis incidence and tumor microvessel density than mice injected with K753M or control. Increased angiogenesis in vivo from the V659E transfectants paralleled increased angiogenic potential in vitro. V659E produced increased vascular endothelial growth factor (VEGF) through increased VEGF protein synthesis. This was mediated through signaling events involving extracellular signal-regulated kinase, phosphatidylinositol 3-kinase/Akt, mammalian target of rapamycin (mTOR), and p70S6K. The V659E xenografts also had significantly increased phosphorylated Akt, phosphorylated p70S6K, and VEGF compared with controls. To validate the clinical relevance of these findings, we examined 155 human breast tumor samples. Human tumors that overexpressed ErbB2, which have been previously shown to have higher VEGF expression, showed significantly higher p70S6K phosphorylation as well. Increased VEGF expression also significantly correlated with higher levels of Akt and mTOR phosphorylation. Additionally, patients with tumors having increased p70S6K phosphorylation showed a trend for worse disease-free survival and increased metastasis. Our findings show that ErbB2 increases VEGF protein production by activating p70S6K in cell lines, xenografts, and in human cancers and suggest that these signaling molecules may serve as targets for antiangiogenic and antimetastatic therapies. ©2006 American Association for Cancer Research.en_HK
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/en_HK
dc.relation.ispartofCancer Researchen_HK
dc.subject.meshAnimalsen_US
dc.subject.meshBreast Neoplasms - Blood Supply - Enzymology - Metabolism - Pathologyen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshFemaleen_US
dc.subject.meshHumansen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Sciden_US
dc.subject.meshMitogen-Activated Protein Kinase Kinases - Metabolismen_US
dc.subject.meshNih 3T3 Cellsen_US
dc.subject.meshNeoplasm Metastasisen_US
dc.subject.meshNeovascularization, Pathologic - Metabolism - Pathologyen_US
dc.subject.meshPhosphatidylinositol 3-Kinases - Metabolismen_US
dc.subject.meshPhosphorylationen_US
dc.subject.meshProtein Kinases - Metabolismen_US
dc.subject.meshProto-Oncogene Proteins C-Akt - Metabolismen_US
dc.subject.meshReceptor, Erbb-2 - Metabolismen_US
dc.subject.meshRibosomal Protein S6 Kinases, 70-Kda - Metabolismen_US
dc.subject.meshTor Serine-Threonine Kinasesen_US
dc.subject.meshTransplantation, Heterologousen_US
dc.subject.meshUp-Regulationen_US
dc.subject.meshVascular Endothelial Growth Factor A - Biosynthesisen_US
dc.titleErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cellsen_HK
dc.typeArticleen_HK
dc.identifier.emailYin, G: gyin@hku.hken_HK
dc.identifier.authorityYin, G=rp00831en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1158/0008-5472.CAN-04-4559en_HK
dc.identifier.pmid16489002-
dc.identifier.scopuseid_2-s2.0-33644529055en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33644529055&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume66en_HK
dc.identifier.issue4en_HK
dc.identifier.spage2028en_HK
dc.identifier.epage2037en_HK
dc.identifier.isiWOS:000235387200022-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridKlos, KS=6602108707en_HK
dc.identifier.scopusauthoridWyszomierski, SL=6507148905en_HK
dc.identifier.scopusauthoridSun, M=14833715200en_HK
dc.identifier.scopusauthoridTan, M=30767796400en_HK
dc.identifier.scopusauthoridZhou, X=7410090129en_HK
dc.identifier.scopusauthoridLi, P=35194423700en_HK
dc.identifier.scopusauthoridYang, W=7407757240en_HK
dc.identifier.scopusauthoridYin, G=8725807500en_HK
dc.identifier.scopusauthoridHittelman, WN=35371136800en_HK
dc.identifier.scopusauthoridYu, D=7404666466en_HK

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