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dc.contributor.authorde Groot, Jolien S
dc.contributor.authorRatze, Max Ak
dc.contributor.authorvan Amersfoort, Miranda
dc.contributor.authorEisemann, Tanja
dc.contributor.authorVlug, Eva J
dc.contributor.authorNiklaas, Mijanou T
dc.contributor.authorChin, Suet-Feung
dc.contributor.authorCaldas, Carlos
dc.contributor.authorvan Diest, Paul J
dc.contributor.authorJonkers, Jos
dc.contributor.authorde Rooij, Johan
dc.contributor.authorDerksen, Patrick Wb
dc.date.accessioned2018-09-10T22:17:31Z
dc.date.available2018-09-10T22:17:31Z
dc.date.issued2018-08
dc.identifier.issn0022-3417
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/280079
dc.description.abstractAlthough mutational inactivation of E-cadherin (CDH1) is the main driver of invasive lobular breast cancer (ILC), approximately 10-15% of all ILCs retain membrane-localized E-cadherin despite the presence of an apparent non-cohesive and invasive lobular growth pattern. Given that ILC is dependent on constitutive actomyosin contraction for tumor development and progression, we used a combination of cell systems and in vivo experiments to investigate the consequences of α-catenin (CTNNA1) loss in the regulation of anchorage independence of non-invasive breast carcinoma. We found that inactivating somatic CTNNA1 mutations in human breast cancer correlated with lobular and mixed ducto-lobular phenotypes. Further, inducible loss of α-catenin in mouse and human E-cadherin-expressing breast cancer cells led to atypical localization of E-cadherin, a rounded cell morphology, and anoikis resistance. Pharmacological inhibition experiments subsequently revealed that, similar to E-cadherin-mutant ILC, anoikis resistance induced by α-catenin loss was dependent on Rho/Rock-dependent actomyosin contractility. Finally, using a transplantation-based conditional mouse model, we demonstrate that inducible inactivation of α-catenin instigates acquisition of lobular features and invasive behavior. We therefore suggest that α-catenin represents a bona fide tumor suppressor for the development of lobular-type breast cancer and as such provides an alternative event to E-cadherin inactivation, adherens junction (AJ) dysfunction, and subsequent constitutive actomyosin contraction. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherWiley
dc.rightsAttribution-NonCommercial 4.0 International (CC BY-NC 4.0)
dc.subjectAdherens Junctions
dc.subjectAnimals
dc.subjectMice, Knockout
dc.subjectHumans
dc.subjectCarcinoma, Lobular
dc.subjectBreast Neoplasms
dc.subjectNeoplasm Invasiveness
dc.subjectGenetic Predisposition to Disease
dc.subjectrho GTP-Binding Proteins
dc.subjectActomyosin
dc.subjectCadherins
dc.subjectTumor Suppressor Proteins
dc.subjectAntigens, CD
dc.subjectCell Adhesion
dc.subjectSignal Transduction
dc.subjectAnoikis
dc.subjectCell Proliferation
dc.subjectCell Shape
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectPhenotype
dc.subjectMutation
dc.subjectFemale
dc.subjectTumor Suppressor Protein p53
dc.subjectalpha Catenin
dc.subjectrho-Associated Kinases
dc.subjectMCF-7 Cells
dc.titleαE-catenin is a candidate tumor suppressor for the development of E-cadherin-expressing lobular-type breast cancer.
dc.typeArticle
prism.endingPage467
prism.issueIdentifier4
prism.publicationDate2018
prism.publicationNameJ Pathol
prism.startingPage456
prism.volume245
dc.identifier.doi10.17863/CAM.27443
dcterms.dateAccepted2018-05-15
rioxxterms.versionofrecord10.1002/path.5099
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-08
dc.contributor.orcidJonkers, Jos [0000-0002-9264-9792]
dc.contributor.orcidDerksen, Patrick Wb [0000-0003-0732-7762]
dc.identifier.eissn1096-9896
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (60098573)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (CB4140)
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idEuropean Commission (258967)
pubs.funder-project-idEuropean Commission FP7 Collaborative projects (CP) (258967)
cam.issuedOnline2018-06-20


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