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Article: Polyomavirus enhancer activator 3 protein promotes breast cancer metastatic progression through Snail-induced epithelial-mesenchymal transition

TitlePolyomavirus enhancer activator 3 protein promotes breast cancer metastatic progression through Snail-induced epithelial-mesenchymal transition
Authors
Issue Date2011
PublisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130
Citation
Journal of Pathology, 2011, v. 224 n. 1, p. 78-89 How to Cite?
AbstractPolyomavirus enhancer activator 3 protein (Pea3), also known as ETV4, is a member of the Ets-transcription factor family, which promotes metastatic progression in various types of solid cancer. Pea3-driven epithelial-mesenchymal transition (EMT) has been described in lung and ovarian cancers. The mechanisms of Pea3-induced EMT, however, are largely unknown. Here we show that Pea3 overexpression promotes EMT in human breast epithelial cells through transactivation of Snail (SNAI1), an activator of EMT. Pea3 binds to the human Snail promoter through the two proximal Pea3 binding sites and enhances Snail expression. In addition, knockdown of Pea3 in invasive breast cancer cells results in down-regulation of Snail, partial reversal of EMT, and reduced invasiveness in vitro. Moreover, knockdown of Snail partially rescues the phenotype induced by Pea3 overexpression, suggesting that Snail is one of the mediators bridging Pea3 and EMT, and thereby metastatic progression of the cancer cells. In four breast cancer patient cohorts whose microarray and survival data were obtained from the Gene Expression Omnibus database, Pea3 and Snail expression are significantly correlated with each other and with overall survival of breast cancer patients. We further demonstrate that nuclear localization of Pea3 is associated with Snail expression in breast cancer cell lines and is an independent predictor of overall survival in a Chinese breast cancer patient cohort. In conclusion, our results suggest that Pea3 may be an important prognostic marker and a therapeutic target for metastatic progression of human breast cancer.
Persistent Identifierhttp://hdl.handle.net/10722/137636
ISSN
2014 Impact Factor: 7.429
2014 SCImago Journal Rankings: 3.612
ISI Accession Number ID
Funding AgencyGrant Number
Cancer Research UK
Funding Information:

This work was funded by the Cancer Research UK China Fellowship to HFY and grant to MET. We would like to thank Professors PS Rudland, R Weinberg, J Hassell, and Y de Launoit for providing us with plasmids and reagents used in this study, and Mr Alan Coffey for technical advice.

References

 

DC FieldValueLanguage
dc.contributor.authorYuen, HFen_HK
dc.contributor.authorChan, YKen_HK
dc.contributor.authorGrills, Cen_HK
dc.contributor.authorMcCrudden, CMen_HK
dc.contributor.authorGunasekharan, Ven_HK
dc.contributor.authorShi, Zen_HK
dc.contributor.authorWong, ASYen_HK
dc.contributor.authorLappin, TRen_HK
dc.contributor.authorChan, KWen_HK
dc.contributor.authorFennell, DAen_HK
dc.contributor.authorKhoo, USen_HK
dc.contributor.authorJohnston, PGen_HK
dc.contributor.authorEl-Tanani, Men_HK
dc.date.accessioned2011-08-26T14:30:00Z-
dc.date.available2011-08-26T14:30:00Z-
dc.date.issued2011en_HK
dc.identifier.citationJournal of Pathology, 2011, v. 224 n. 1, p. 78-89en_HK
dc.identifier.issn0022-3417en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137636-
dc.description.abstractPolyomavirus enhancer activator 3 protein (Pea3), also known as ETV4, is a member of the Ets-transcription factor family, which promotes metastatic progression in various types of solid cancer. Pea3-driven epithelial-mesenchymal transition (EMT) has been described in lung and ovarian cancers. The mechanisms of Pea3-induced EMT, however, are largely unknown. Here we show that Pea3 overexpression promotes EMT in human breast epithelial cells through transactivation of Snail (SNAI1), an activator of EMT. Pea3 binds to the human Snail promoter through the two proximal Pea3 binding sites and enhances Snail expression. In addition, knockdown of Pea3 in invasive breast cancer cells results in down-regulation of Snail, partial reversal of EMT, and reduced invasiveness in vitro. Moreover, knockdown of Snail partially rescues the phenotype induced by Pea3 overexpression, suggesting that Snail is one of the mediators bridging Pea3 and EMT, and thereby metastatic progression of the cancer cells. In four breast cancer patient cohorts whose microarray and survival data were obtained from the Gene Expression Omnibus database, Pea3 and Snail expression are significantly correlated with each other and with overall survival of breast cancer patients. We further demonstrate that nuclear localization of Pea3 is associated with Snail expression in breast cancer cell lines and is an independent predictor of overall survival in a Chinese breast cancer patient cohort. In conclusion, our results suggest that Pea3 may be an important prognostic marker and a therapeutic target for metastatic progression of human breast cancer.en_HK
dc.languageengen_US
dc.publisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130en_HK
dc.relation.ispartofJournal of Pathologyen_HK
dc.rightsJournal of Pathology. Copyright © John Wiley & Sons.-
dc.subject.meshTumor Markers, Biological - metabolismen_HK
dc.subject.meshTumor Cells, Cultureden_HK
dc.subject.meshTranscription Factors - genetics - physiologyen_HK
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction - methodsen_HK
dc.subject.meshProto-Oncogene Proteins - metabolism - physiologyen_HK
dc.subject.meshPromoter Regions, Geneticen_HK
dc.subject.meshPrognosisen_HK
dc.subject.meshNeoplasm Proteins - metabolism - physiologyen_HK
dc.subject.meshNeoplasm Metastasisen_HK
dc.subject.meshNeoplasm Invasivenessen_HK
dc.subject.meshHumansen_HK
dc.subject.meshGene Knockdown Techniquesen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshEpithelial-Mesenchymal Transition - physiologyen_HK
dc.subject.meshAdenovirus E1A Proteins - metabolism - physiologyen_HK
dc.subject.meshBreast Neoplasms - genetics - metabolism - pathologyen_HK
dc.subject.meshEpithelial-Mesenchymal Transition - physiologyen_HK
dc.subject.meshProto-Oncogene Proteins - metabolism - physiologyen_HK
dc.subject.meshTranscription Factors - genetics - physiologyen_HK
dc.titlePolyomavirus enhancer activator 3 protein promotes breast cancer metastatic progression through Snail-induced epithelial-mesenchymal transitionen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1096-9896 (Electronic) 0022-3417 (Linkin&volume=224&issue=1&spage=78&epage=89&date=2011&atitle=Polyomavirus+enhancer+activator+3+protein+promotes+breast+cancer+metastatic+progression+through+Snail-induced+epithelial-mesenchymal+transitionen_US
dc.identifier.emailYuen, HF: h9931179@hku.hken_HK
dc.identifier.emailChan, YK: ykchanc@hku.hken_HK
dc.identifier.emailWong, ASY: ashley@pathology.hku.hk-
dc.identifier.emailChan, KW: hrmtckw@hku.hk-
dc.identifier.emailKhoo, US: uskhoo@hkucc.hku.hk-
dc.identifier.emailEl-Tanani, M: m.el-tanani@qub.ac.uk-
dc.identifier.authorityChan, KW=rp00330en_HK
dc.identifier.authorityKhoo, US=rp00362en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/path.2859en_HK
dc.identifier.pmid21404275en_HK
dc.identifier.scopuseid_2-s2.0-79953767723en_HK
dc.identifier.hkuros191721en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79953767723&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume224en_HK
dc.identifier.issue1en_HK
dc.identifier.spage78en_HK
dc.identifier.epage89en_HK
dc.identifier.eissn1096-9896-
dc.identifier.isiWOS:000289440400009-
dc.publisher.placeUnited Kingdomen_HK

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