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Article: Polyomavirus enhancer activator 3 protein promotes breast cancer metastatic progression through Snail-induced epithelial-mesenchymal transition
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TitlePolyomavirus enhancer activator 3 protein promotes breast cancer metastatic progression through Snail-induced epithelial-mesenchymal transition
 
AuthorsYuen, HF2
Chan, YK1
Grills, C2
McCrudden, CM2
Gunasekharan, V2
Shi, Z2 3
Wong, ASY1
Lappin, TR2
Chan, KW1
Fennell, DA2
Khoo, US1
Johnston, PG2
El-Tanani, M2
 
Issue Date2011
 
PublisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130
 
CitationJournal of Pathology, 2011, v. 224 n. 1, p. 78-89 [How to Cite?]
DOI: http://dx.doi.org/10.1002/path.2859
 
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.
 
ISSN0022-3417
2013 Impact Factor: 7.330
 
DOIhttp://dx.doi.org/10.1002/path.2859
 
ISI Accession Number IDWOS:000289440400009
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.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorYuen, HF
 
dc.contributor.authorChan, YK
 
dc.contributor.authorGrills, C
 
dc.contributor.authorMcCrudden, CM
 
dc.contributor.authorGunasekharan, V
 
dc.contributor.authorShi, Z
 
dc.contributor.authorWong, ASY
 
dc.contributor.authorLappin, TR
 
dc.contributor.authorChan, KW
 
dc.contributor.authorFennell, DA
 
dc.contributor.authorKhoo, US
 
dc.contributor.authorJohnston, PG
 
dc.contributor.authorEl-Tanani, M
 
dc.date.accessioned2011-08-26T14:30:00Z
 
dc.date.available2011-08-26T14:30:00Z
 
dc.date.issued2011
 
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.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationJournal of Pathology, 2011, v. 224 n. 1, p. 78-89 [How to Cite?]
DOI: http://dx.doi.org/10.1002/path.2859
 
dc.identifier.doihttp://dx.doi.org/10.1002/path.2859
 
dc.identifier.eissn1096-9896
 
dc.identifier.epage89
 
dc.identifier.hkuros191721
 
dc.identifier.isiWOS:000289440400009
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.

 
dc.identifier.issn0022-3417
2013 Impact Factor: 7.330
 
dc.identifier.issue1
 
dc.identifier.openurl
 
dc.identifier.pmid21404275
 
dc.identifier.scopuseid_2-s2.0-79953767723
 
dc.identifier.spage78
 
dc.identifier.urihttp://hdl.handle.net/10722/137636
 
dc.identifier.volume224
 
dc.languageeng
 
dc.publisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofJournal of Pathology
 
dc.relation.referencesReferences in Scopus
 
dc.rightsJournal of Pathology. Copyright © John Wiley & Sons.
 
dc.subject.meshTumor Markers, Biological - metabolism
 
dc.subject.meshTumor Cells, Cultured
 
dc.subject.meshTranscription Factors - genetics - physiology
 
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction - methods
 
dc.subject.meshProto-Oncogene Proteins - metabolism - physiology
 
dc.subject.meshPromoter Regions, Genetic
 
dc.subject.meshPrognosis
 
dc.subject.meshNeoplasm Proteins - metabolism - physiology
 
dc.subject.meshNeoplasm Metastasis
 
dc.subject.meshNeoplasm Invasiveness
 
dc.subject.meshHumans
 
dc.subject.meshGene Knockdown Techniques
 
dc.subject.meshFemale
 
dc.subject.meshEpithelial-Mesenchymal Transition - physiology
 
dc.subject.meshAdenovirus E1A Proteins - metabolism - physiology
 
dc.subject.meshBreast Neoplasms - genetics - metabolism - pathology
 
dc.subject.meshEpithelial-Mesenchymal Transition - physiology
 
dc.subject.meshProto-Oncogene Proteins - metabolism - physiology
 
dc.subject.meshTranscription Factors - genetics - physiology
 
dc.titlePolyomavirus enhancer activator 3 protein promotes breast cancer metastatic progression through Snail-induced epithelial-mesenchymal transition
 
dc.typeArticle
 
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<contributor.author>Gunasekharan, V</contributor.author>
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<subject.mesh>Tumor Markers, Biological - metabolism</subject.mesh>
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<subject.mesh>Transcription Factors - genetics - physiology</subject.mesh>
<subject.mesh>Reverse Transcriptase Polymerase Chain Reaction - methods</subject.mesh>
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Author Affiliations
  1. The University of Hong Kong
  2. Queen's University Belfast
  3. Kingston University