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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 - 197
dc.identifier.issn1061-4036
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4682
dc.identifier.eissn1546-1718
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.
dc.formatPrint-Electronic
dc.format.extent187 - 197
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectAnimals
dc.subjectMice, Inbred NOD
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectCell Cycle Proteins
dc.subjectDNA-Binding Proteins
dc.subjectEstrogen Receptor alpha
dc.subjectTranscription Factors
dc.subjectXenograft Model Antitumor Assays
dc.subjectCell Proliferation
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectAcetylation
dc.subjectDrug Resistance, Neoplasm
dc.subjectFemale
dc.subjectHepatocyte Nuclear Factor 3-alpha
dc.subjectHistone Deacetylase 1
dc.subjectMCF-7 Cells
dc.subjectClustered Regularly Interspaced Short Palindromic Repeats
dc.titleARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response.
dc.typeJournal Article
dcterms.dateAccepted2019-11-01
rioxxterms.versionAM
rioxxterms.versionofrecord10.1038/s41588-019-0541-5
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature genetics
pubs.issue2
pubs.notesNot known
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.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-statusPublished
pubs.volume52
pubs.embargo.termsNot known
icr.researchteamPreclinical Modelling of Paediatric Cancer Evolution
icr.researchteamPreclinical Modelling of Paediatric Cancer Evolutionen_US
dc.contributor.icrauthorBruna Cabot, Alejandraen


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