乳腺癌的分子生物学进展(1)

BreastcarcinomasCancerandcardiovasculardiseasesaretheleadingcausesofdeatharoundtheworld.Cancersarisingintissuessuchasstomach,liver,lung,breast,nasopharynxandbonemarrowareverycommoninChina.(AdaptedfromJemalA,etal:Cancerstatistics,2003.CACancerJClin53:5,2003.)EpidemiologyWorldwide,themostcommonmalignanttumorsinmalesarecancersoflung,stomach,liver,colon/rectumandesophagus.Worldwide,themostcommonmalignanttumorsinfemalesarecancersofbreast,lung,stomach,colon/rectumandcervix.WHO20072007CSCOAnnualMeeting(2007年全国临床肿瘤学大会)InChina,themostcommonmalignanttumorsinmalesarecancersoflung,stomach,liver,colon/rectumandesophagus.InChina,themostcommonmalignanttumorsinfemalesarecancersofbreast,lung,colon/rectum,stomachandliver.BreastcarcinomaBreastcarcinomaisthemostcommonmalignancyinwomen.Awomanwholivestoage90hasaoneineightchanceofdevelopingbreastcancer.EpidemiologyStudyofcancerpatternsinpopulations,cancerepidemiology,cancontributesubstantiallytoknowledgeabouttheoriginsofcancer.Part1BreastcancerriskfactorsWell-confirmedfactorsProbablefactorsFactor1:Geographiclocationlow-risk:FarEast,AfricaandSouthAmericahigh-risk:NorthAmericaandNorthernEuropeareas.EpidemiologyFactor2:AgeBreastcancerisrarelyfoundbeforetheageof25yearsexceptincertainfamilialcases.Theincidencerisesthroughoutawoman'slifetime.Seventy-sevenpercentofcasesoccurinwomenover50yearsofage.Theaverageageatdiagnosisis64years.Factor3:EarlyAgeofMenarcheWomenwhoreachmenarchewhenyoungerthan12yearsofagehavea20%increasedriskcomparedtowomenwhoreachmenarchewhenmorethan14yearsofage.Itisprobablybecauseofaprolongedexposureofbreastepitheliumtoestrogensandprogesteroneduetoearlierregularovulatorymenstrualcycles.Factor4:LateAgeofMenopauseLatemenopause(54)alsoincreasesrisk,butthemagnitudeoftheriskhasnotbeenquantified.Incontrast,surgically-inducedmenopause(ovariectomyorhysterectomy)beforetheageof35resultsinadecreaseofbreastcancerrisk.Evenunilateralovariectomyperformedbeforetheageof45hasbeendemonstratedtobeprotective.Factor5:NulliparityandolderageatfirstlivebirthWomenwithafirstfull-termpregnancyatyoungerthan20yearsofagehavehalftheriskofnulliparouswomenorwomenovertheageof35attheirfirstbirth.Interestingly,womenwiththeirfirstbirthafterageof35areevenathigherriskthannulliparouswomen.Onemechanismmayinvolveamarkedlyreducedsusceptibilityofthefullymammaryglandtocarcinogens,duetoinpartadecreaseinproliferativeactivityofparous(经产的)epithelium.Anotherpossibilityisduetothealteredhormonalenvironmentduringpregnancy(e.g.decreaseincirculatinggrowthfactorhormoneetc).Factor6:FamilyhistoryofbreastcancerWomenwithone,two,andthreeormorefirst-degreeaffectedrelativeshaveanincreasedbreastcancerriskwhencomparedwithwomenwhodonothaveanaffectedrelative(riskratios1.8,2.9and3.9,respectively)•Breastcanceroccurringbeforeage50(premenopausal)infirst-orsecond-degreerelative(s)•Twoormorefirst-orsecond-degreerelativeswithbreastorovariancancer•Oneormorefirst-,second-,orthird-degreerelative(s)withbreastandovariancancerorwithtwoseparateorindependentbreastcancers•Malerelative(s)withbreastcancer•Oneormorefirst-,second-,orthird-degreerelative(s)withBRCA1and/orBRCA2genemutationNote.First-degreerelativesaremother,daughter,sister,father,son,andbrother.Second-degreerelativesaregrandmother,aunt,niece,grandfather,uncle,andnephew.Third-degreerelativesaregreat-grandmother,great-grandfather,great-aunt,great-uncle,andfemaleandmalefirstcousins.Figure1.FamilyHistoryThatIncreasesBreastCancerRiskHereditaryBreastCancerAbout25%offamilialbreastcancers(oraround3%ofallbreastcancers)canbeattributedtotwohighlypenetrantautosomaldominantgenes:BRCA1andBRCA2.About10%offamilialbreastcancersareattributedtop53,PTEN,CHEK2,ATMgenes.Factor7:IntakeofExogenoushormonesPostmenopausalhormonereplacementtherapyincreasestheriskofbreastcancerdependingonthedurationofexposureandwhethertheestrogenisusedaloneorincombinationwithprogestin.Whentakingoralcontraceptive,womenwithafamilyhistoryhaveasignificantincreaseinbreastcancerrisk.HormoneactsasapromoterKnudsonproposedthatcarcinogenesisrequirestwophases.Thefirsteventisinitiation(激发),andthecarcinogencausingitistheinitiator.Thesecondevent,whichinducesneoplasticgrowth,ispromotion(促进),andtheagentisthepromoter.AdaptedfromKumar:RobbinsandCotran:PathologicBasisofDiseaseFigure:Initiationandpromotionofaneoplasm.Polycyclichydrocarbons(多环烃),whicharecarcinogensathighdoses,causeskincancer.Theactionofpolycyclichydrocarbonsisenhancedbycrotonoil(巴豆油),whichactsasapromoter.Thisisbestseenbytheeffectofcrotonoilinproducingcancerwhenasubcarcinogenic(low)doseofpolycyclichydrocarbonisused.Notethatcrotonoilinanydosedoesnotcausecancer.ManycarcinogensactasbothinitiatorsandpromotersCarcinogenicagentsInitiationandpromotionInitiationcausespermanentDNAdamage(mutations).Itisrapidandirreversibleandhasmemory.Aninitiatedcellispotentiallycapableofgivingrisetoatumor.Initiationalone,however,isnotsufficientfortumorformation.Promoterscaninducetumorsininitiatedcells,buttheyarenontumorigenicbythemselves.Thecellularchangesresultingfromtheapplicationofpromot