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Article: Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors

TitleUpregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors
Authors
KeywordsBreast cancer
ErbB2
Invasion
Metastasis
PKCα
Src
Issue Date2006
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2006, v. 25 n. 23, p. 3286-3295 How to Cite?
AbstractAlthough ErbB2 is known to enhance breast cancer metastasis, the signaling events responsible for this remain elusive. α-Isozyme of protein kinase C (PKCα), which is involved in cancer development and progression, has been suggested to be activated by ErbB2 without direct evidence. In addition, the roles of PKCα in ErbB2-mediated cancer cell malignancy have not been clearly identified. In this study, we investigated whether ErbB2 can activate PKCα and determined what role PKCα plays in ErbB2-mediated breast cancer cell invasion. We expressed wild-type and mutant ErbB2 with altered signaling capacities in MDA-MB-435 breast cancer cells and revealed that overexpression or activation of ErbB2 in MDA-MB-435 cells upregulated and activated PKCα and that downregulation of ErbB2 by small-interfering RNA decreased the expression and activity of PKCα in BT474 breast cancer cells. These in vitro results were supported by data from breast cancer patient samples. In 150 breast cancer tumor samples, ErbB2-overexpressing tumors showed significantly higher positive rates of PKCα membrane immunohistochemistry staining than that of ErbB2-low-expressing tumors. Mechanistically, we found that PKCα is co-immunoprecipitated with Src and PKCα expression and activity can be decreased by Src inhibitor PP2 and by the expression of a dominant-negative mutant of Src. Moreover, ErbB2-mediated upregulation of urokinase-type plasminogen activator receptor (uPAR) is reduced by either the PKCα inhibitor Go6976 or the Src inhibitor PP2, and the combination of Go6976 with PP2 is superior to either agent alone in suppressing uPAR expression and cell invasion. These results demonstrate that PKCα is critical for ErbB2-mediated cancer cell invasion and provide valuable insights for current and future PKCα and Src inhibitor clinical trials. © 2006 Nature Publishing Group All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/146576
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorTan, Men_HK
dc.contributor.authorLi, Pen_HK
dc.contributor.authorSun, Men_HK
dc.contributor.authorYin, Gen_HK
dc.contributor.authorYu, Den_HK
dc.date.accessioned2012-05-02T08:37:08Z-
dc.date.available2012-05-02T08:37:08Z-
dc.date.issued2006en_HK
dc.identifier.citationOncogene, 2006, v. 25 n. 23, p. 3286-3295en_HK
dc.identifier.issn0950-9232en_HK
dc.identifier.urihttp://hdl.handle.net/10722/146576-
dc.description.abstractAlthough ErbB2 is known to enhance breast cancer metastasis, the signaling events responsible for this remain elusive. α-Isozyme of protein kinase C (PKCα), which is involved in cancer development and progression, has been suggested to be activated by ErbB2 without direct evidence. In addition, the roles of PKCα in ErbB2-mediated cancer cell malignancy have not been clearly identified. In this study, we investigated whether ErbB2 can activate PKCα and determined what role PKCα plays in ErbB2-mediated breast cancer cell invasion. We expressed wild-type and mutant ErbB2 with altered signaling capacities in MDA-MB-435 breast cancer cells and revealed that overexpression or activation of ErbB2 in MDA-MB-435 cells upregulated and activated PKCα and that downregulation of ErbB2 by small-interfering RNA decreased the expression and activity of PKCα in BT474 breast cancer cells. These in vitro results were supported by data from breast cancer patient samples. In 150 breast cancer tumor samples, ErbB2-overexpressing tumors showed significantly higher positive rates of PKCα membrane immunohistochemistry staining than that of ErbB2-low-expressing tumors. Mechanistically, we found that PKCα is co-immunoprecipitated with Src and PKCα expression and activity can be decreased by Src inhibitor PP2 and by the expression of a dominant-negative mutant of Src. Moreover, ErbB2-mediated upregulation of urokinase-type plasminogen activator receptor (uPAR) is reduced by either the PKCα inhibitor Go6976 or the Src inhibitor PP2, and the combination of Go6976 with PP2 is superior to either agent alone in suppressing uPAR expression and cell invasion. These results demonstrate that PKCα is critical for ErbB2-mediated cancer cell invasion and provide valuable insights for current and future PKCα and Src inhibitor clinical trials. © 2006 Nature Publishing Group All rights reserved.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/oncen_HK
dc.relation.ispartofOncogeneen_HK
dc.subjectBreast canceren_HK
dc.subjectErbB2en_HK
dc.subjectInvasionen_HK
dc.subjectMetastasisen_HK
dc.subjectPKCαen_HK
dc.subjectSrcen_HK
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols - Pharmacologyen_US
dc.subject.meshBreast Neoplasms - Drug Therapy - Enzymology - Pathologyen_US
dc.subject.meshCarbazoles - Pharmacologyen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshEnzyme Activation - Drug Effects - Physiologyen_US
dc.subject.meshFemaleen_US
dc.subject.meshHumansen_US
dc.subject.meshIndoles - Pharmacologyen_US
dc.subject.meshNeoplasm Invasiveness - Pathology - Prevention & Controlen_US
dc.subject.meshNeoplasm Metastasis - Drug Therapy - Prevention & Controlen_US
dc.subject.meshProtein Kinase C-Alpha - Antagonists & Inhibitors - Biosynthesis - Metabolismen_US
dc.subject.meshProtein Kinase Inhibitors - Pharmacologyen_US
dc.subject.meshProto-Oncogene Proteins Pp60(C-Src) - Antagonists & Inhibitors - Physiologyen_US
dc.subject.meshPyrimidines - Pharmacologyen_US
dc.subject.meshReceptor, Erbb-2 - Physiologyen_US
dc.subject.meshReceptors, Cell Surface - Antagonists & Inhibitors - Biosynthesisen_US
dc.subject.meshReceptors, Urokinase Plasminogen Activatoren_US
dc.subject.meshUp-Regulation - Drug Effectsen_US
dc.titleUpregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitorsen_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.doi10.1038/sj.onc.1209361en_HK
dc.identifier.pmid16407820-
dc.identifier.scopuseid_2-s2.0-33744936606en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33744936606&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume25en_HK
dc.identifier.issue23en_HK
dc.identifier.spage3286en_HK
dc.identifier.epage3295en_HK
dc.identifier.isiWOS:000237951200007-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridTan, M=30767796400en_HK
dc.identifier.scopusauthoridLi, P=35194423700en_HK
dc.identifier.scopusauthoridSun, M=14833715200en_HK
dc.identifier.scopusauthoridYin, G=8725807500en_HK
dc.identifier.scopusauthoridYu, D=7404666466en_HK
dc.identifier.citeulike480158-

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