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Overcoming chemoresistance in triple negative breast cancer by bromodomain inhibition

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dc.contributor.coauthorPhilpott, M.
dc.contributor.coauthorCribbs, A.
dc.contributor.coauthorOppermann, U.
dc.contributor.coauthorOnder, T. T.
dc.contributor.departmentDepartment of Molecular Biology and Genetics
dc.contributor.departmentGraduate School of Health Sciences
dc.contributor.departmentSchool of Medicine
dc.contributor.kuauthorAksu, Ali Cenk
dc.contributor.kuauthorAyhan, Ceyda Açılan
dc.contributor.kuauthorBayram, Özlem Yedier
dc.contributor.kuauthorCevatemre, Buse
dc.contributor.kuauthorCingöz, Ahmet
dc.contributor.kuauthorDeğirmenci, Nareg Pınarbaşı
dc.contributor.kuauthorEsin, Beril
dc.contributor.kuauthorKayabölen, Alişan
dc.contributor.kuauthorÖnder, Tuğba Bağcı
dc.contributor.schoolcollegeinstituteCollege of Engineering
dc.contributor.schoolcollegeinstituteCollege of Sciences
dc.contributor.schoolcollegeinstituteGRADUATE SCHOOL OF HEALTH SCIENCES
dc.contributor.schoolcollegeinstituteSCHOOL OF MEDICINE
dc.date.accessioned2024-11-09T23:39:18Z
dc.date.issued2022
dc.description.abstractBackground: Triple negative breast cancer (TNBC) is an aggressive subtypeofbreastcancerwithpoorprognosis.TNBCcellsdonotexpress receptorsforestrogen,progesteroneorHer2,eliminatingthepossibilityof targetedtherapyapplications.Therefore,current treatmentoptionforTNBC is limitedwithsurgery followedbyconventional chemotherapy.However, acquiredresistancetochemotherapyisamajorchallengethatisassociated withrelapse,whichisdrivenbycoordinatedactionsofgeneticandepigenetic events. MaterialsandMethods:Weaimedtoelucidatetherolesoffullspectrum ofepigeneticmodifiersinmaintenanceandreversionofchemoresistancein TNBC.TogenerateinvitromodelsofchemoresistantTNBC,weexposed3 different TNBC cell lines to escalating doses of taxane (paclitaxel). Transcriptome analysis by RNA-sequencingwere performed to reveal changesthat regulatechemoresistance.Withourcustomepigenome-wide CRISPR-Cas9library(EpigeneticKnock-OutLibrary-EPIKOL)targetingall chromatinreaders,writers,erasersandassociatedproteins,wesystematicallyinterrogatedtherolesofepigeneticmodifiersinchemoresistantTNBC cells.Wealsoconductedmediumscalechemicalscreensutilizingepigenetic probelibrariesinchemoresistantcells. Results:RNAsequencingonpairedsensitiveandchemoresistancecell linesrevealedABCB1upregulationasamajordriverofresistance.Inhibition of themembersofMLLandSWI/SNFcomplexes, aswell as thegenes relatedwithhistoneubiquitinationandacetyl-mark readers re-sensitized chemoresistantcellstopaclitaxel.Amemberof thebromodomainprotein family,BRPF1,cameasacommonhit inourchemical screenaswellas geneticscreens.KnockoutofBRPF1or itschemical inhibitioncompletely abolishedpaclitaxel resistanceandmodulatedABCB1expression. Conclusions:ThroughEPIKOLscreensonchemoresistantTNBCcells coupledwithchemicalscreens,weidentifiednovelepigeneticmodifiersthat arecrucial formaintainingandovercomingdrug resistance.Collectively, thesefindingsprovideabasistodevelopcombinationtherapiestoefficiently killchemoresistantTNBC.
dc.description.indexedbyWOS
dc.description.indexedbyScopus
dc.description.openaccessNO
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuN/A
dc.description.sponsorshipScientific and Technological Research Council of Turkey (TUBITAK) [1003- 216S461] This work was supported by The Scientific and Technological Research Council of Turkey (TUBITAK) 1003- 216S461 Grant
dc.description.volume174
dc.identifier.eissn1879-0852
dc.identifier.issn0959-8049
dc.identifier.scopus2-s2.0-85143781807
dc.identifier.urihttps://hdl.handle.net/20.500.14288/13076
dc.identifier.wos876973400176
dc.keywordsEpigenetics
dc.keywordsBreast cancer
dc.keywordsDrug resistance
dc.language.isoeng
dc.publisherElsevier Sci Ltd
dc.relation.ispartofEuropean Journal of Cancer
dc.subjectOncology
dc.titleOvercoming chemoresistance in triple negative breast cancer by bromodomain inhibition
dc.typeMeeting Abstract
dspace.entity.typePublication
local.contributor.kuauthorBayram, Özlem Yedier
local.contributor.kuauthorCingöz, Ahmet
local.contributor.kuauthorAksu, Ali Cenk
local.contributor.kuauthorDeğirmenci, Nareg Pınarbaşı
local.contributor.kuauthorEsin, Beril
local.contributor.kuauthorKayabölen, Alişan
local.contributor.kuauthorCevatemre, Buse
local.contributor.kuauthorAyhan, Ceyda Açılan
local.contributor.kuauthorÖnder, Tuğba Bağcı
local.publication.orgunit1College of Engineering
local.publication.orgunit1GRADUATE SCHOOL OF HEALTH SCIENCES
local.publication.orgunit1SCHOOL OF MEDICINE
local.publication.orgunit1College of Sciences
local.publication.orgunit2Department of Molecular Biology and Genetics
local.publication.orgunit2School of Medicine
local.publication.orgunit2Graduate School of Health Sciences
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