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dc.contributor.authorNagarajan, S
dc.contributor.authorRao, SV
dc.contributor.authorSutton, J
dc.contributor.authorCheeseman, D
dc.contributor.authorDunn, S
dc.contributor.authorPapachristou, EK
dc.contributor.authorPrada, J-EG
dc.contributor.authorCouturier, D-L
dc.contributor.authorKumar, S
dc.contributor.authorKishore, K
dc.contributor.authorChilamakuri, CSR
dc.contributor.authorGlont, S-E
dc.contributor.authorArcher Goode, E
dc.contributor.authorBrodie, C
dc.contributor.authorGuppy, N
dc.contributor.authorNatrajan, R
dc.contributor.authorBruna, A
dc.contributor.authorCaldas, C
dc.contributor.authorRussell, A
dc.contributor.authorSiersbæk, R
dc.contributor.authorYusa, K
dc.contributor.authorChernukhin, I
dc.contributor.authorCarroll, JS
dc.date.accessioned2021-07-13T15:19:00Z
dc.date.available2021-07-13T15:19:00Z
dc.identifier.citationNature genetics, 2020, 52 (2), pp. 187 - 197en_US
dc.identifier.issn1061-4036
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4682
dc.identifier.eissn1546-1718en_US
dc.identifier.eissn1546-1718
dc.identifier.doi10.1038/s41588-019-0541-5en_US
dc.identifier.doi10.1038/s41588-019-0541-5
dc.description.abstractUsing genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screens to understand endocrine drug resistance, we discovered ARID1A and other SWI/SNF complex components as the factors most critically required for response to two classes of estrogen receptor-alpha (ER) antagonists. In this context, SWI/SNF-specific gene deletion resulted in drug resistance. Unexpectedly, ARID1A was also the top candidate in regard to response to the bromodomain and extraterminal domain inhibitor JQ1, but in the opposite direction, with loss of ARID1A sensitizing breast cancer cells to bromodomain and extraterminal domain inhibition. We show that ARID1A is a repressor that binds chromatin at ER cis-regulatory elements. However, ARID1A elicits repressive activity in an enhancer-specific, but forkhead box A1-dependent and active, ER-independent manner. Deletion of ARID1A resulted in loss of histone deacetylase 1 binding, increased histone 4 lysine acetylation and subsequent BRD4-driven transcription and growth. ARID1A mutations are more frequent in treatment-resistant disease, and our findings provide mechanistic insight into this process while revealing rational treatment strategies for these patients.en_US
dc.formatPrint-Electronicen_US
dc.format.extent187 - 197en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_US
dc.subjectAnimalsen_US
dc.subjectMice, Inbred NODen_US
dc.subjectHumansen_US
dc.subjectBreast Neoplasmsen_US
dc.subjectCell Cycle Proteinsen_US
dc.subjectDNA-Binding Proteinsen_US
dc.subjectEstrogen Receptor alphaen_US
dc.subjectTranscription Factorsen_US
dc.subjectXenograft Model Antitumor Assaysen_US
dc.subjectCell Proliferationen_US
dc.subjectGene Expression Regulation, Neoplasticen_US
dc.subjectAcetylationen_US
dc.subjectDrug Resistance, Neoplasmen_US
dc.subjectFemaleen_US
dc.subjectHepatocyte Nuclear Factor 3-alphaen_US
dc.subjectHistone Deacetylase 1en_US
dc.subjectMCF-7 Cellsen_US
dc.subjectClustered Regularly Interspaced Short Palindromic Repeatsen_US
dc.titleARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-11-01
rioxxterms.versionAMen_US
rioxxterms.versionofrecord10.1038/s41588-019-0541-5en_US
dc.relation.isPartOfNature geneticsen_US
pubs.issue2en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Preclinical Modelling of Paediatric Cancer Evolution
pubs.publication-statusPublisheden_US
pubs.volume52en_US
pubs.embargo.termsNot knownen_US
icr.researchteamPreclinical Modelling of Paediatric Cancer Evolution
dc.contributor.icrauthorBruna Cabot, Alejandraen_US


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