PDLIM2 is a marker of adhesion and β-catenin activity in triple-negative breast cancer

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dc.contributor.authorCox, Orla T.
dc.contributor.authorEdmunds, Shelley J.
dc.contributor.authorSimon-Keller, Katja
dc.contributor.authorLi, Bo
dc.contributor.authorMoran, Bruce
dc.contributor.authorBuckley, Niamh E.
dc.contributor.authorBustamante- Garrido, Milán F.
dc.contributor.authorHealy, Nollaig
dc.contributor.authorO'Flanagan, Ciara H.
dc.contributor.authorGallagher, William M.
dc.contributor.authorKennedy, Richard D.
dc.contributor.authorBernards, René
dc.contributor.authorCaldas, Carlos
dc.contributor.authorChin, Suet-Feung
dc.contributor.authorMarx, Alexander
dc.contributor.authorO'Connor, Rosemary
dc.contributor.funderIrish Cancer Societyen
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderSeventh Framework Programmeen
dc.date.accessioned2019-06-12T10:57:34Z
dc.date.available2019-06-12T10:57:34Z
dc.date.issued2019-03-18
dc.date.updated2019-06-12T10:43:53Z
dc.description.abstractThe PDLIM2 protein regulates stability of transcription factors including NF-κB and STATs in epithelial and hemopoietic cells. PDLIM2 is strongly expressed in certain cancer cell lines that exhibit an Epithelial-to-Mesenchymal phenotype, and its suppression is sufficient to reverse this phenotype. PDLIM2 supports the epithelial polarity of non-transformed breast cells, suggesting distinct roles in tumor suppression and oncogenesis. To better understand its overall function, we investigated PDLIM2 expression and activity in breast cancer. PDLIM2 protein was present in 60% of tumors diagnosed as triple-negative breast cancer (TNBC), and only 20% of other breast cancer subtypes. High PDLIM2 expression in TNBC was positively correlated with adhesion signaling and β-catenin activity. Interestingly, PDLIM2 was restricted to the cytoplasm/membrane of TNBC cells and excluded from the nucleus. In breast cell lines, PDLIM2 retention in the cytoplasm was controlled by cell adhesion, and translocation to the nucleus was stimulated by IGF-1 or TGFβ. Cytoplasmic PDLIM2 was associated with active β-catenin and ectopic expression of PDLIM2 was sufficient to increase β-catenin levels and its transcriptional activity in reporter assays. Suppression of PDLIM2 inhibited tumor growth in vivo, whereas over-expression of PDLIM2 disrupted growth in 3D cultures. These results suggest that PDLIM2 may serve as a predictive biomarker for a large subset of TNBC whose phenotype depends on adhesion-regulated β-catenin activity and which may be amenable to therapies that target these pathways.en
dc.description.sponsorshipIrish Cancer Society (Collaborative Cancer Research Centre BREAST-PREDICT CCRC13GAL); Science Foundation Ireland (Principal Investigator awards 11/PI/11139 and 16IA4505)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationCox, O. T., Edmunds, S. J., Simon-Keller, K., Li, B., Moran, B., Buckley, N. E., Bustamante-Garrido, M., Healy, N., O'Flanagan, C. H., Gallagher, W. M., Kennedy, R. D., Bernards, R., Caldas, C., Chin, S.-F., Marx, A. and O'Connor, R. (2019) ‘PDLIM2 is a marker of adhesion and β-catenin activity in triple-negative breast cancer', Cancer Research, 79(10), pp. 2619-2633. doi: 10.1158/0008-5472.CAN-18-2787en
dc.identifier.doi10.1158/0008-5472.CAN-18-2787en
dc.identifier.eissn1538-7445
dc.identifier.endpage2633en
dc.identifier.issn0008-5472
dc.identifier.issued10en
dc.identifier.journaltitleCancer Researchen
dc.identifier.startpage2619en
dc.identifier.urihttps://hdl.handle.net/10468/8050
dc.identifier.volume79en
dc.language.isoenen
dc.publisherAmerican Association for Cancer Researchen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP3::PEOPLE/251480/EU/Identification of Clinically Useful Biomarkers for IGF-I Receptor Signalling n Cancer/BIOMARKERIGFen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::HEALTH/258967/EU/Rational Therapy for Breast Cancer: Individualized Treatment for Difficult-to-Treat Breast Cancer Subtypes/RATHERen
dc.relation.urihttp://cancerres.aacrjournals.org/content/79/10/2619
dc.rights© 2019, American Association for Cancer Research. All rights reserved.en
dc.subjectPredictive biomarkeren
dc.subjectPDLIM2en
dc.subjectTriple-negative breast canceren
dc.subjectTNBCen
dc.subjectAdhesion-regulated β-catenin activityen
dc.titlePDLIM2 is a marker of adhesion and β-catenin activity in triple-negative breast canceren
dc.typeArticle (peer-reviewed)en
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