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

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dc.contributor.author Cox, Orla T.
dc.contributor.author Edmunds, Shelley J.
dc.contributor.author Simon-Keller, Katja
dc.contributor.author Li, Bo
dc.contributor.author Moran, Bruce
dc.contributor.author Buckley, Niamh E.
dc.contributor.author Bustamante- Garrido, Milán F.
dc.contributor.author Healy, Nollaig
dc.contributor.author O'Flanagan, Ciara H.
dc.contributor.author Gallagher, William M.
dc.contributor.author Kennedy, Richard D.
dc.contributor.author Bernards, René
dc.contributor.author Caldas, Carlos
dc.contributor.author Chin, Suet-Feung
dc.contributor.author Marx, Alexander
dc.contributor.author O'Connor, Rosemary
dc.date.accessioned 2019-06-12T10:57:34Z
dc.date.available 2019-06-12T10:57:34Z
dc.date.issued 2019-03-18
dc.identifier.citation Cox, 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-18-2787 en
dc.identifier.volume 79 en
dc.identifier.issued 10 en
dc.identifier.startpage 2619 en
dc.identifier.endpage 2633 en
dc.identifier.issn 0008-5472
dc.identifier.uri http://hdl.handle.net/10468/8050
dc.identifier.doi 10.1158/0008-5472.CAN-18-2787 en
dc.description.abstract The 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.sponsorship Irish Cancer Society (Collaborative Cancer Research Centre BREAST-PREDICT CCRC13GAL); Science Foundation Ireland (Principal Investigator awards 11/PI/11139 and 16IA4505) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher American Association for Cancer Research en
dc.relation.uri http://cancerres.aacrjournals.org/content/79/10/2619
dc.rights © 2019, American Association for Cancer Research. All rights reserved. en
dc.subject Predictive biomarker en
dc.subject PDLIM2 en
dc.subject Triple-negative breast cancer en
dc.subject TNBC en
dc.subject Adhesion-regulated β-catenin activity en
dc.title PDLIM2 is a marker of adhesion and β-catenin activity in triple-negative breast cancer en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Rosemary O'Connor, Biochemistry & Cell Biology, University College Cork, Cork, Ireland. +353-21-490-3000 Email: r.oconnor@ucc.ie en
dc.internal.availability Full text available en
dc.check.info Access to this article is restricted until 12 months after publication by request of the publisher. en
dc.check.date 2020-03-18
dc.date.updated 2019-06-12T10:43:53Z
dc.description.version Accepted Version en
dc.internal.rssid 481883629
dc.internal.pmid 30885980
dc.contributor.funder Irish Cancer Society en
dc.contributor.funder Science Foundation Ireland en
dc.contributor.funder Seventh Framework Programme en
dc.description.status Peer reviewed en
dc.identifier.journaltitle Cancer Research en
dc.internal.copyrightchecked Yes
dc.internal.licenseacceptance Yes en
dc.internal.IRISemailaddress r.oconnor@ucc.ie en
dc.relation.project info:eu-repo/grantAgreement/EC/FP7::SP3::PEOPLE/251480/EU/Identification of Clinically Useful Biomarkers for IGF-I Receptor Signalling n Cancer/BIOMARKERIGF en
dc.relation.project info:eu-repo/grantAgreement/EC/FP7::SP1::HEALTH/258967/EU/Rational Therapy for Breast Cancer: Individualized Treatment for Difficult-to-Treat Breast Cancer Subtypes/RATHER en
dc.identifier.eissn 1538-7445

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