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dc.contributor.authorWang, Y
dc.contributor.authorBernhardy, AJ
dc.contributor.authorCruz, C
dc.contributor.authorKrais, JJ
dc.contributor.authorNacson, J
dc.contributor.authorNicolas, E
dc.contributor.authorPeri, S
dc.contributor.authorvan der Gulden, H
dc.contributor.authorvan der Heijden, I
dc.contributor.authorO'Brien, SW
dc.contributor.authorZhang, Y
dc.contributor.authorHarrell, MI
dc.contributor.authorJohnson, SF
dc.contributor.authorCandido Dos Reis, FJ
dc.contributor.authorPharoah, PDP
dc.contributor.authorKarlan, B
dc.contributor.authorGourley, C
dc.contributor.authorLambrechts, D
dc.contributor.authorChenevix-Trench, G
dc.contributor.authorOlsson, H
dc.contributor.authorBenitez, JJ
dc.contributor.authorGreene, MH
dc.contributor.authorGore, M
dc.contributor.authorNussbaum, R
dc.contributor.authorSadetzki, S
dc.contributor.authorGayther, SA
dc.contributor.authorKjaer, SK
dc.contributor.authorkConFab Investigators
dc.contributor.authorD'Andrea, AD
dc.contributor.authorShapiro, GI
dc.contributor.authorWiest, DL
dc.contributor.authorConnolly, DC
dc.contributor.authorDaly, MB
dc.contributor.authorSwisher, EM
dc.contributor.authorBouwman, P
dc.contributor.authorJonkers, J
dc.contributor.authorBalmaña, J
dc.contributor.authorSerra, V
dc.contributor.authorJohnson, N
dc.date.accessioned2017-05-03T15:01:17Z
dc.date.issued2016-05
dc.identifier.citationCancer research, 2016, 76 (9), pp. 2778 - 2790
dc.identifier.issn0008-5472
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/634
dc.identifier.eissn1538-7445
dc.identifier.doi10.1158/0008-5472.can-16-0186
dc.description.abstractBreast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo Furthermore, spliceosome inhibitors reduced BRCA1-Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance. Cancer Res; 76(9); 2778-90. ©2016 AACR.
dc.formatPrint
dc.format.extent2778 - 2790
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectkConFab Investigators
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectBreast Neoplasms
dc.subjectOvarian Neoplasms
dc.subjectCisplatin
dc.subjectBRCA1 Protein
dc.subjectProtein Isoforms
dc.subjectFluorescent Antibody Technique
dc.subjectBlotting, Western
dc.subjectImmunohistochemistry
dc.subjectXenograft Model Antitumor Assays
dc.subjectPolymerase Chain Reaction
dc.subjectAlternative Splicing
dc.subjectDrug Resistance, Neoplasm
dc.subjectGerm-Line Mutation
dc.subjectFemale
dc.subjectPoly(ADP-ribose) Polymerase Inhibitors
dc.titleThe BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin.
dc.typeJournal Article
dcterms.dateAccepted2016-02-15
rioxxterms.versionofrecord10.1158/0008-5472.can-16-0186
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2016-05
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer research
pubs.issue9
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished
pubs.volume76
pubs.embargo.termsNo embargo
dc.contributor.icrauthorGore, Martinen


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