mentsenom

13FundamentalPathwaysinBreastCancer2:MaintenanceofGenomicStabilityChiaraGorriniandTakW.
Mak2.
1IntroductionMammaliancellspreservetheirgenomicintegritybycoun-teractingDNAdamage[1].
DNAdamagecanoriginatefromexogenousandendogenousinsults.
Exogenousinsultsinvolveenvironmentalstressthatoriginatesfromexposuretochemicals,UVlight,tobaccosmoke,chemotherapy,andradiotherapy.
EndogenousDNAdamagecanarisefromimpairedDNAmetabolicprocesses,intracellularoxidativestress,andoncogeneactivation.
CellsrespondtoDNAdam-agebyactivatingsensors,transducers,andeffectorsthatjointlycoordinatetheso-calledDNAdamageresponse(DDR).
WhentheamountofDNAdamageismanageable,DDRactivatescellcyclecheckpointsthatarrestcellcycleprogressionandallowDNArepairtocorrectthelesionthuspreventingreplicationofdamagedDNA.
WhenDNAdam-agereacheslevelsbeyondrepair,cellsactivateself-destructionmechanismsthatincludeapoptosis,autophagy,senescence,andnecrosis.
TherearefivedifferentmechanismsofrepairdesignedforspecifictypesofDNAlesions[2]:Baseexcisionrepair(BER)removesbasedamage.
BERismainlyinvolvedinthesurveillance,recognition,andrepairofoxidativeDNA.
Mismatchrepair(MMR)correctsreplicativeerrorsandmismatchedbasepairscausedbyfaultyproofreadingofDNApolymerases.
MMRensureslowmutationratesinreplicatingcells.
Nucleotideexcisionrepair(NER)operatesonaspectrumofhelix-destabilizingbulkyDNAlesions(globalgenomeNERorGG-NER)oreliminateslesionsinthetranscribedstrandofactivegenes(transcription-coupledNERorTC-NER).
Forexample,NERremovesbulkyDNAadductscausedbyexposuretovariouschemicals,alkylatingagents,andUVradiation.
Single-strandbreak(SSB)DNArepaircorrectsDNAbreaksononestrandoftheDNAdoublehelixarisingdirectlyonthedeoxyribosemoietiesorindirectlyasinter-mediatesofBER.
SSBsareamongthemostfrequentDNAlesionsandaremajorthreatstogeneticstabilityandcellsurvival.
Double-strandbreak(DSB)DNArepairresolveslesionsthatappearonbothDNAstrands.
TheDSBistheprinci-plelesionderivingfromionizingradiationandradiomi-meticchemicals.
ItisalsocausedwhenareplicativeDNApolymeraseencountersaDNAsingle-strandbreakorothertypeofDNAlesions.
DSBsareintermediatesinvariousbiologicalevents,suchasV(D)JrecombinationindifferentiatingBcells.
TherearetwomajorpathwaysofDSBrepair:homologousrecombination(HR)andnonho-mologousendjoining(NHEJ).
DuringHR,therepairofthedamagedstrandoccursbyretrievinggeneticinforma-tionfromtheundamagedcomplementaryDNAsisterstrand.
Incontrast,NHEJbringsabouttheligationoftwoDNADSBswithouttherequirementforsequencehomol-ogybetweentheDNAends.
Althoughthesemechanismsaretightlyregulated,DNArepairdefectsoccurtherebypromotingtheacquisitionofmutations.
GenomicinstabilityresultsfromahighfrequencyofDNAmutationsrangingfromnucleotidechangestochro-mosomaltranslocation,anditisacommonfeatureofmanycancers.
Denovogeneticalterationscaninitiatetumorigen-esis,augmentaggressiveness,andultimatelyaffecttheover-allprognosisofcancerpatients.
RecentstudieshaveshownthatdifferenttumorshavespecificDNArepairdefectsigna-turesthatinvolvemorethanonerepairpathway[3].
AmorecomprehensiveanalysisofthesesignatureshasshownthatDNArepairmechanismsarenotparalleldistinctentitiesbutareintimatelyinterconnectedandcaninfluenceeachother.
WhileanormalcellcoordinatesDNArepairtopreserveitsgenomicintegrity,cancercellsmodifyDNArepairhubsto2C.
GorriniT.
W.
Mak(*)TheCampbellFamilyInstituteforBreastCancerResearch,PrincessMargaretCancerCentre,Toronto,ON,Canadae-mail:tmak@uhnres.
utoronto.
ca14maintaingenomicinstabilitywithoutcompromisingsur-vival.
Infact,cancercellsaresubjectedtomanystressfulconditionsincludingnutrientstarvation,oxidativestress,hypoxia,chemotherapy,andradiationthatultimatelyresultingenotoxicdamage.
Therefore,acancercellmustrelyonacertainleveloffunctionalDNArepairtocopewiththeseadditionalsourcesofdamage.
RegulationofDDRandDNArepairhasacriticalroleinthedevelopmentandtreatmentofbreastcancer.
Expressionandgenomicprofilingstudieshaveshownthatbreastcancerisaveryheterogeneousdisease[4].
Therearedifferentsub-typesofbreastcancers,andeachtypeexhibitsarangeofbio-logicalandclinicalbehaviors(discussedmoreindetailinChap.
1.
4).
LuminalsubtypesAandBbothexpressmarkersoftheluminalepitheliallayerofnormalbreasttissuesuchaskeratins8/18andareestrogenreceptor(ER)positive.
TheERBB2subtypeischaracterizedbytheamplificationandoverexpressionofERBB2(HER2)andneighboringgenesat17q12-q21locus.
Thebasal-likesubtypeexpressesmarkersofthebasalepitheliallayerofnormalbreasttissuesuchaskeratins5/6.
CancercellsofthissubtypedonotexpressER,progesteronereceptor(PR),andHER2andarethereforereferredtoastriplenegative(TN).
OtherTNtypesinclude"normal-like"andtherecentlydescribed"claudin-low"sub-type,showingthatmostbutnotallTNarebasal-likecancers.
Therearetwomainhypothesesthatcanexplaintheexistenceofdifferentsubtypes:(1)eachsubtypearisesfromadistincttumor-initiatingcelland(2)allsubtypesshareacommoncelloforiginthateventuallyacquireddifferentsomaticDNAmutationsleadingtodifferentbiologicalphenotypes.
Althoughadefinitiveanswerislackingandbothphenomenacancoexist,itisclearthatbreastcancersubtypesaretheresultsofdistinctevolutionaryprocesses.
Thegenomicpro-fileofbreastcancersspansfromarelativelysimplelandscapeinluminalAsubtypetoahighlycomplexscenarioinbasal-like/TNsubtype(Fig.
2.
1).
Inthischapter,wewillconsidertheroleofgenomicinstabilityunderlyingthedifferentbio-logicalandclinicalfeaturesofeachbreastcancersubtype.
2.
2GenomicInstabilityinLuminalA/BSubtypesofBreastCancersLuminalAandBsubtypessharesimilarbiologicalcharacter-istics.
However,luminalBtumorsaremoregeneticallyunsta-bleandhighlyproliferativeandhavelessfavorableprognosis.
LuminalAsubtypetumorshavefewchromosomerearrange-mentsthatdefinea"simple"genomiclandscape.
Themainfeatureofthispatternisgainofchromosome1pand16pwithlossof16q[5].
LuminalBsubtypehasadifferentpatternofgenomicalterationscalled"amplifier"or"firestorm.
"Thispatternischaracterizedbyfocalhigh-levelDNAamplifica-tions,clusteredononeormorechromosomearm[6].
MostofluminalBDNArearrangementsaffecttheexpressionofgenesinvolvedinsignaling,cellcycleregulation,andnucleicacidmetabolismsuchasFGFR1,MYC,CCND1,MDM2,ERBB2,andZNF217.
Inthesetumorcells,theamplifiedDNAcanexisteitherasrepeatedunitswithinchromosomescalledhomogeneouslystainingregions(HSRs)orasextra-chromosomalcopiescalled"doubleminutes.
"SeveralstudieshavedemonstratedthepresenceofgenomicinstabilityinluminalA/Bcancers.
CyclinD1,oneofthemostamplifiedgenesinluminalBcancer,contributestotumorprogressionbyactivatingatranscriptionalprogramthatpromoteschromosomalinstability(CIN)[7].
Theanaly-sisofalargedatasetofhumanspecimenhasshownthat52%ofluminalA/BtumorsoverexpressthegeneESPL1thatencodesforaseparase,aproteasethatcleavesthechromo-somalcohesinduringmitosis[8].
Indeed,overexpressionofESPL1inthemousemammaryglandinduceschromosomalinstabilityandaneuploidy[9].
Genomicdatafromover1000luminalAtumorshasidentifiedfourmajorsubtypesdefinedbydistinctcopynumberandmutationprofiles.
Amongthesetypes,thisgrouphascharacterizedanatypicalluminalAsubtypecharacterizedbyhighergenomicinstability,TP53mutations,andincreasedaurorakinasesignalingassociatedwithworseclinicalprognosis[5].
Moreover,arecentstudyhasshownthatinearly-stageluminalbreastcarcinoma,genomicinstability,definedasahighnumberofchromo-somalbreakpoints,isastrongerprognosticmarkerthanpro-liferation[10].
Overall,thesestudiessuggestthatgenomiccomplexityisafeatureofluminalbreastcancerandcanbeusedtopredicttheoutcomeofthesetumors.
2.
3GenomicInstabilityinERBB2SubtypeofBreastCancersERBB2tumorsubtypehasagenomiclandscapethatissimi-lartoluminalBsubtype.
Itischaracterizedbyan"amplifier"genomicpatternwithfocalhigh-levelDNAamplifications[6].
However,differentfromluminalBsubtype,amplificationLuminalA"simple"LuminalB,ERBB2"amplifier"Basal-like,TNBC"complex"PrognosisGenomicinstabilityFig.
2.
1Correlationbetweentumoraggressivenessandgenomicinstabilityinthedifferentsubtypesofbreastcancer.
LuminalAsubtypetendstohavegoodprognosisanda"simple"genomiclandscapewithfewgeneticalterations.
LuminalBandERBB2subtypeshavean"amplifier"genomewithhighfrequencyofgeneduplications.
Asaconsequence,theirprognosisislessfavorablethanluminalA.
Basal-likeandTNbreastcancershaveahighlyunstable"complex"genomicprofileandhaveverypoorprognosis15of17q12(ERBB2)isthemostprominentamplificationeventinERBB2subtype.
TheamplificationofERBB2geneseemstoderivefromasisterchromatidbreakage-fusion-bridgeprocessbasedontheanalysisofanERBB2-amplifiedbreastcancerline[11].
SeveralstudieshaverevealedadirectlinkbetweenERBB2oncogeneandfactorsinvolvedinthemaintenanceofgenomicintegrity.
Forexample,theanalysisofacollectionofERBB2-positivebreastcancercellssuggeststhepresenceofcentrosomeamplificationwithincreasedproteinexpres-sionofthecentrosomekinasesNek2andPlk4[12].
Also,expressionofERBB2inimmortalizedbreastepithelialcellsdownregulatestheDNAdamagesensorproteinhistoneH2AXandanumberofothercomponentsoftheHRandNHEJdouble-strandDNAbreakrepairpathways[13].
Overall,thesepreclinicalmodelsindicatearoleforERBB2signalingininitiatingCINanddefectivecellcyclecontrol.
2.
4GenomicInstabilityinBasal-LikeandTripleNegativeSubtypesofBreastCancersBasal-likeandtriplenegative(TN)breastcancershaveanextremelycomplexgenomicpattern.
Theirgenomeincludesnumerousgains,losses,andsmalltandemduplicationsresultinginahighlysegmentedprofilewithmanycopynum-bertransitions.
Inthislandscapeaprominentplaceisoccu-piedbythetumorsuppressorBRCA1.
ThegeneBRCA1isoneofthemostimportantDNArepairfactorsandcontrolsHR-directedDNArepair[14].
StrongsimilaritiesexistbetweenbreastcancersbearingBRCA1mutationandspo-radicbasal-likebreastcancers,underlyingtheinherentlygenomicinstabilityofthisparticularcancersubtype.
GermlinemutationsthatinactivateBRCA1predisposewomentobreastcancerswithbasal-like/TNfeatures[15].
Inthesetumors,dysfunctionofHRrepairleadstoincreasederror-pronerepair,whichresultsinchromosomerearrange-mentsandcopynumbertransitions.
AlthoughBRCA1ismainlyknownforitsroleinDNArepair,ithasseveralotherbiologicalfunctionsthatcontributetotumorpredisposition.
BRCA1controlsbreastepithelialdifferentiation,regulatingthedifferentiationofER-negativebreastepithelialstemcellsintoER-positiveluminalprogenitors[16].
ThisstudyhasopenedadebateonthecelloforiginofBRCA1-associatedbreastcancers.
Forexample,thebreasttissueofwomencarryingBRCA1mutationsarecharacterizedbyabnormalaccumulationofluminalprogenitors,supportingtheideathatbasal-liketumorsmayoriginatefromacancer-initiatingcellwithluminalfeatures[17].
Indeed,deletionofBRCA1inmousemammaryepithelialluminalprogenitorsproducestumorsthatphenocopyhumanBRCA1breastcancers[18].
Recently,weidentifiedBRCA1asanovelregulatorofcellularantioxidantresponse[19].
Inthisstudy,cellscarry-ingBRCA1loss-of-functionmutationsaccumulateoxidativestressthataffectssurvival.
Thisiscounteractedbytheactiva-tionofoneofthemostimportantpro-survivalprogramsinthecells,thePI3Kpathway(seeChap.
1.
1fordetails),andcontrolledbyestrogenthatrestoresantioxidantdefenseandpromotessurvivalandmalignanttransformation[20].
ThesedataclarifiedtheroleofestrogeninBRCA1/TNBCassug-gestedbyothermouseandhumanstudies[21,22].
BRCA1isnottheonlyDNArepairfactorassociatedwithbasal-likebreastcancers.
OtherproteinsinvolvedinDDRandDNArepairhavebeenidentified.
Thesefactorsaretrans-ducers(ATMandATR)oreffectors(Chk2)ofDDRandrepairfactors(Rad51andPALB2).
Becausebasal-likeandTNbreastcancersareassociatedwithaverycomplexgeneticlandscape,effectivetreatmentofthisparticularsubtypeofbreastcancerstillrepresentsachal-lengeforclinicians.
Therefore,scientistsaredevotingtheireffortstoidentifyspecificvulnerabilitiesthatguidetomoretargetedtherapeuticapproaches.
Forexample,basal-likeandTNbreastcancersseemtorelyontheactivationofPI3Ksig-nalingpathwayforcellgrowthandsurvival[23].
ThelossofPTEN,thenegativeregulatorofPI3K,isaveryfrequentgeneticeventinthesetumors[24].
Indeed,basal-likeandTNbreastcancersareparticularlysensitivetoPI3Kinhibitors,suchasBKM120[25].
TheactivationofPARP-mediatedDNArepair(SSBandBER)isanothermechanismofadapta-tionthatoccursinBRCA1-mutatedcancersthatareHRdefective[26].
PARPinhibitorshaveproventobeparticularlyeffectiveinthesetumors,mainlyincombinationwithPI3Kinhibitors[27].
Ourgrouphasidentifiedanotherdependencyofbasal-likeandTNbreastcancersthatinvolvestheactivityoftheserine/threonineproteinkinasePLK4[28].
ThisworkhasledtotheidentificationofCFI-400945,apotentandselectivePLK4inhibitor,particularlyeffectiveintumorswithPTENdeficiency.
Overall,basal-likeandTNbreastcancersarecharacterizedbyhighdegreeofgenomicinstabilitycom-paredtootherbreastcancersubtypes.
Althoughgenomicinstabilitycanproducealterationsthatarebeneficialfortumorgrowth,itcanalsocreatevulnerabilities.
Importantly,genomicinstabilitycangenerate"syntheticlethal"interac-tionsthatcanbeexploitedtherapeutically.
ConclusionsAsdiscussedinthischapter,breastcancerisaverycom-plexdiseasewithdifferentbiologicalandgeneticfeatures.
Thestudyofbreastcancergenomesandgenomicinstabil-ityisadvancingrapidlythankstomoreadvancedgenomictechnologies,butmuchremainstobelearned.
Forexample,itisunclearwhichrolegenomicinstabilityhasintheclonalevolutionofbreastcancer.
Genomicinstabilitycanbethegeneraldrivingforceofbreastcancerorsimplyaconse-16quenceofthespecificmutationsthatcharacterizeeachsub-type(Fig.
2.
2).
Inthefirsthypothesis,allsubtypewouldshareacommoncelloforiginthatacquiresacertainlevelofgenomicinstabilityupongenotoxicdamage.
Thismuta-torlandscapewouldfavorstochasticacquisitionsofmuta-tionsinspecificgenessuchasERBB2thatwouldgiverisetoeachsubtype.
Inthesecondhypothesis,eachsubtypewouldoriginatefromadifferentcellthatwillstochasticallyacquiremutationsinspecificgenessuchasERBB2.
Basedonwhichpathwaywillbealtered,eachsubtypewillshowadifferentdegreeofgenomicinstability.
Bothhypotheseswellsupporttheheterogeneityofbreastcancerdisease.
Therecentdevelopmentofsingle-cellsequencingmayrevealanotherlayerofcomplexity,thatis,intra-tumoralheterogeneity.
Thisanalysiscanbeusedtoidentifyandcharacterizehiddensubpopulationsandshedlightontheclonalevolutionofbreastcancer.
Clonaldynamicsshouldbestudiedinresponsetocancertherapytofurtherevaluatemechanismsofadaptations.
Currently,computationalbiol-ogistsandbioinformaticshavedevelopedtoolsthatareabletohandlehugeamountofdata.
Thetaskforcancerresearchscientistsistodevelopbiologicalmodelssuitabletoreveal"drivers"and"vulnerabilities"intheoverwhelmingland-scapeofcancercomplexity.
Althoughadvantageous,livingwithgenomicinstabilityisachallengethatcancercellsfacebytriggeringmechanismsofadaptation.
Theidentifi-cationofthesemechanismswillrevealnovelvulnerabili-tiesforbetter-tailoredtherapies.
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