Essential function for PDLIM2 in cell polarization in three-dimensional cultures by feedback regulation of the β1-Integrin–RhoA signaling axis

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dc.contributor.authorDeevi, Ravi Kiran
dc.contributor.authorCox, Orla T.
dc.contributor.authorO'Connor, Rosemary
dc.contributor.funderBreast Cancer Campaignen
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderHealth Research Boarden
dc.contributor.funderIrish Cancer Societyen
dc.date.accessioned2018-07-10T09:38:10Z
dc.date.available2018-07-10T09:38:10Z
dc.date.issued2014-05
dc.date.updated2018-07-10T09:25:51Z
dc.description.abstractPDLIM2 is a cytoskeletal and nuclear PDZ-LIM domain protein that regulates the stability of Nuclear Factor kappa-B (NF kappa B) and other transcription factors, and is required for polarized cell migration. PDLIM2 expression is suppressed by methylation in different cancers, but is strongly expressed in invasive breast cancer cells that have undergone an Epithelial Mesenchymal Transition (EMT). PDLIM2 is also expressed in non-transformed breast myoepithelial MCF10A cells and here we asked whether it is important for maintaining the polarized, epithelial phenotype of these cells. Suppression of PDLIM2 in MCF10A cells was sufficient to disrupt cell polarization and acini formation with increased proliferation and reduced apoptosis in the luminal space compared to control acini with hollow lumina. Spheroids with suppressed PDLIM2 exhibited increased expression of cell-cell and cell-matrix adhesion proteins including beta 1 (beta 1) integrin. Interestingly, levels of the Insulin-like growth factor 1 receptor (IGF-1 R) and Receptor of activated protein kinase C 1 (RACK1), which scaffolds IGF-1R to beta 1 integrin, were also increased, indicating a transformed phenotype. Focal Adhesion Kinase (FAK) and cofilin phosphorylation, and RhoA Guanosine Triphosphatase (GTPase) activity were all enhanced in these spheroids compared to control acini. Importantly, inhibition of either FAK or Rho Kinase (ROCK) was sufficient to rescue the polarity defect. We conclude that PDLIM2 expression is essential for feedback regulation of the beta 1-integrin-RhoA signalling axis and integration of cellular microenvironment signals with gene expression to control the polarity of breast epithelial acini structures. This is a mechanism by which PDLIM2 could mediate tumour suppression in breast epithelium.en
dc.description.sponsorshipBreast Cancer Campaign (2008NovPR24); Health Research Board (HRA 2009/41); Science Foundation Ireland (PI awards 07/INI/Β107 and 11/PI/1136); Irish Cancer Society (Collaborative Cancer Research Centre BREAST-PREDICT)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationDeevi, K.R., Cox, O.T. and O'Connor, R. (2014) 'Essential function for PDLIM2 in cell polarization in three-dimensional cultures by feedback regulation of the β1-Integrin–RhoA signaling axis'. Neoplasia, 16 (5):422-431. DOI: 10.1016/j.neo.2014.04.006en
dc.identifier.doi10.1016/j.neo.2014.04.006
dc.identifier.endpage431en
dc.identifier.issn1522-8002
dc.identifier.issued5en
dc.identifier.journaltitleNeoplasiaen
dc.identifier.startpage422en
dc.identifier.urihttps://hdl.handle.net/10468/6444
dc.identifier.volume16en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Principal Investigator Programme (PI)/11/PI/1139/IE/IGF-I Receptor signalling and regulation/en
dc.relation.urihttp://www.sciencedirect.com/science/article/pii/S1476558614000451
dc.rights© 2014 Neoplasia Press, Inc. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectInsulin-like-growthen
dc.subjectIGF-1 receptoren
dc.subjectNf-kappa-ben
dc.subjectAnchorage-independent growthen
dc.subjectDomain-containing protein-2en
dc.subjectTo-mesenchymal transitionen
dc.subjectMammary epithelial-cellsen
dc.subjectBreast-canceren
dc.subjectExtracellular-matrixen
dc.subjectInteracting proteinen
dc.titleEssential function for PDLIM2 in cell polarization in three-dimensional cultures by feedback regulation of the β1-Integrin–RhoA signaling axisen
dc.typeArticle (peer-reviewed)en
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