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Genetic Polymorphisms in Steroid Hormone Metabolizing Enzymes In TurkJMedSci 32(2002)217-221 ©TÜB‹TAK NeslihanAYGÜNKOCABAfi GeneticPolymorphismsinSteroidHormone MetabolizingEnzymesinHumanBreastCancer Abstract: Epidemiologicstudiesindicatethat metabolism(i.e., CYP17,CYP19,CYP1A1, Received:July04,2001 mostriskfactorsforbreastcancerarerelated CYP1B1,MnSOD,COMT,andGST)thatmay toreproductiveandhormonalfactors.The accountforaproportionofenzymatic evaluationofassociationsbetweenbreast variability.Anevaluationofassociations cancerriskandgeneticpolymorphismsin betweenbreastcancerriskandgenetic enzymesinvolvedinhormonemetabolism polymorphismsinenzymesinvolvedin maybeacosteffectivemannerinwhichto hormonemetabolismisdescribedinthisbrief determineindividualbreastcancer review. susceptibility.Anumberofmolecular DepartmentofToxicology,Facultyof epidemiologicstudieshavebeenconductedto evaluateassociationsbetweenpolymorphic KeyWords : Breastcancer,Genetic Pharmacy,GaziUniversity06330Hipodrom polymorphism,Steroidhormonemetabolism Ankara,Turkey genesinvolvedinsteroidhormone Breastcanceristhemostcommonlyoccurringcancer Metabolicactivationof17 β-estradiol(E2)hasbeen amongwomen,andthemorbidityrateofthisdisease postulatedtobeafactorinmammarycarcinogenesis.E2 continuestorise,whereasthemortalityrateisdeclining ismetabolizedviatwomajorpathways:formationof duetomoreadvanceddiagnosisandtreatment catecholestrogens,the2-OHand4-OHderivates;andC- techniques(1).Fewerbreastcancercasescanbe 16α hydroxylation(Figure).The2-OHand4-OHcatechol explainedbyrare,highlypenetrantgenessuchasBRCA1, estrogensareoxidizedtosemiquinonesandquinones. BRCA2 andTP53.Inprinciple,common,lowpenetrance Thelatterarereactiveelectrophilicmetabolitesandare genescouldexplainthemajorityofbreastcancercases capableofformingDNAadducts.FurtherDNAdamage (2). resultsfromquinone-semiquinoneredoxcycling, Endogenoussteroidhormonesareimportantinthe generatedbyenzymaticreductionofcatecholestrogen developmentandprogressionofbreastcancer.Steroid quinonestosemiquinonesandsubsequentauto-oxidation α hormonesexertgrowth-promotingeffectsandinduce backtoquinones.C-16 hydroxylationhasalsobeen breastcellproliferationbybindingtointracellular suggestedtobeinvolvedinbreastcarcinogenesis(6). receptorsandregulatinggenetranscription(3).Several Geneticpolymorphismhasbeenfoundtobethebasis breastcancerriskfactorsarethoughttoactby offrequentlyobservedindividualvariationinactivitiesof influencinglifetimeexposuretosteroidhormones.The drugmetabolizingenzymesamonghumanpopulations. rateofincreaseinbreastcancerincidencedeclinesafter Strikingethnicdissimilarities,aswellasinter-individual menopause,probablyduetolowercirculatingestrogen differences,ingenesinvolvedindrugmetabolismarewell andprogestronelevels.Ageatmenarche,ageat known(7).Asobservedindrugandchemicalmetabolism, menopause,postmenopausalobesity,and thereisconsiderableinter-individualgeneticvariabilityin postmenopausalhormoneusearewell-establishedbreast themetabolicandbiosyntheticpathwaysin cancerriskfactorsthatinfluencethedoseanddurationof steroidogenesis(5).Manyoftheenzymesinvolvedin estrogenandprogestroneexposure(4). estrogenmetabolismarepolymorphicallydistributed Onceformed,estrogensareextensivelymetabolized withinthehumanpopulation(i.e., CYP17,CYP19, byanumberofoxidativeandconjugatereactionsthatcan CYP1A1,CYP1B1,MnSOD,COMT, and GST)(5,8). leadtotheirdeactivationandsubsequentelimination(5). Inheritedalterationsintheactivityofanyofthese 217 GeneticPolymorphismsinSteroidHormoneMetabolizingEnzymesinHumanBreastCancer Cholesterol CYP11α (20,22-Lyase) 17α-Hydroxypregnenolone Dehydroepi- Progesterone andosterone CYP17 CYP17 (17α-Hydroxylase) 17-20-Lyase Progesterone 17α-Hydroxypregnenolone Androstendione Testosterone CYP21 (21α-Hydroxylase) CYP18 (Aromatase) 11-Deoxycorticosterone 11-Deoxycortoisol 20H-estradiol CYP11β (11β-Hydroxylase) 17β-HSD CYP1A1 Corticosterone Cortisol Esterone Estradiol 4OH-estradiol CYP1B1 18-Hydroxylase Estrone silpfatase 16OH-estradiol Estronesulfate Aldosterone Figure. Theestradiolsynthesismetabolicpathway(8) enzymesholdthepotentialtodefinedifferencesinbreast ThecytochromeP450enzyme P45017 hasboth cancerriskassociatedwithestrogencarcinogenesis. 17α-hydroxylaseand17,20-lyaseactivitiesandcatalyzes However,itisevidentthatnosinglegenotypecanbe twodistinctstepsinsteroidhormoneproduction.In linkedtoallbreastcancers.Knowngenetic steroidogenesis,ageneencodingthesteroidogenic polymorphismsinsteroidhormonemetabolizingenzymes enzyme17 α-hydroxylaseconvertspregnenoloneand inhumanbreastcancerareshownintheTable. progesteroneto17-hydroxypregnenoloneand17- Table. KnownGeneticPolymorphismsinSteroidHormoneMetabolizingEnzymesinHumanBreastCancer(5,8) Enzyme RoleinEstrogenMetabolism Allelicvariants CYP17 17-α hydroxylase/C17-20lyase,catalyzesrate-limiting Twovariants,enhancedpromoteractivity stepinovarianandadrenalbiosynthesispathwaysfor androstenedione CYP19 Aromatase/estrogensynthetase,convertstestosteroneand Fourteenvariants,mayaltersplicesite androstenedionetoE2andE1,respectively andabilityofconvertingactivity CYP1A1 2-hydroxylase,generates2-OHCE Fourvariants,changedactivity CYP1B1 4-hydroxylase,generates4-OHCE Sevenvariants,changedactivity MnSOD Manganesesuperoxidedismutase,converts2superoxide Twovariants,alteredproteintrafficking radicalstoH2O2 andO2 COMT Methyltransferase,methylatesandinactivatesCE Twovariants,decreasedmethylationactivity GST Glutathionesulfotransferases,decreasesoxidativestress GSTM1,deletionoftheentiregene,thenullallele generatedduringestrogenmetabolism GSTT1,deletionoftheentiregene,thenullallele GSTP1,twovariants,reducedactivity 218 N.AYGÜNKOCABAfi hydroxyprogesterone,respectively.Inwomen, acidsubstitutions.Twooftheseaminoacidsubstitutions P450c17α isprimarilyexpressedinovarianthecacells havebeendescribedinexon3,whichencodestheheme- andadrenalcortex. CYP17 containsasingle-base bindingdomain:codon432Val →Leuandcodon453 polymorphismthatcreatesaSP1-type(CCACCbox) Asn→Ser;andtheothertwoincodon48Arg →Glyand promoterandalsogeneratesallelescorrelatingwith 119Ala →Serinexon2(15).Polymorphismsare differentpromoteractivity(9).Raremutationsinthe inheritedalterationsintheactivityof CYP1B1 thathold codingregionof CYP17 haverecentlybeenassociated thepotentialtodefinedifferencesinestrogenmetabolism withbreastcancerrisk.StudiessuggestthattheA2allele and,thereby,possiblyexplaininter-individualdifferences ofCYP17 elevatesendogenoushormonelevels,butisnot inbreastcancerriskassociatedwithestrogen-mediated astrongindependentriskfactorforbreastcancer(10). carcinogenesis(16). Thearomataseenzymecatalyzestheconversionof Superoxidedismutase(Mn,Cu,ZnSOD)catalyzesthe androgenstoestrogensintheestrogenbiosynthesis dismutationoftwosuperoxideradicals,producing pathway.Becauseincreasedexposuretoestrogenis hydrogenperoxideandoxygen,becauseROS,including consideredtobeariskfactorforbreastcancer, thosegeneratedbyestrogensandtheirmetabolites,may polymorphichumanaromatasegene( CYP19)isa beinvolvedinbreastcarcinogenesisandbecause MnSOD plausiblecandidateforlowpenetrancebreastcancer isamajorenzymeinvolvedinthescavengingoffree susceptibility(5).Thepolymorphicrepeat(TTTA)in radicals(5).Anaminoacidexchangeatthe9positionof intron5,TCTinsertion/deletioninintron4,anda MnSOD inthesignalpeptidesequenceapparentlyalters substitutioninintron6ofthe CYP19 genecreate14 thestructureoftheenzyme,affectingitsabilitytoenter allelesinwhichtochangearomataseactivity.Although themitochondrion.MnSOD alanineallelecouldberelated therehavebeennumerousreportsofdifferentTTTA tobreastcancerriskbyhavinganalteredcapacityto repeatallelesbeingassociatedwithvariationsinbreast reduceoxidativestress(17). cancerrisk,the CYP19 genehasnomajorrolein SeveralPhaseIIenzymeseitherinactivateCEsor commonbreastcancerincidence(11). protectagainstestrogencarcinogenesisbydetoxifying Inthebreast, CYP1A1 and CYP1B1 areresponsible productsofoxidativedamagethatmayariseonredox forthehydroxylationofestrogenstothe2-hydroxy cyclingofCEs.Geneticvariantsofeachoftheseenzymes estrogen(2-OHHE)and4-OHHEs.Inturn, CYP1B1 involvedinCEmetabolismhavebeenidentified,some exceeds CYP1A1 initscatalyticefficiencyasE2 withprovenorsuspectedchangeinfunction.Catechol-O- hydroxylaseanddiffersfromCYP1A1 initsprincipalsite methyltransferase( COMT)isoneofseveralphaseII ofcatalysis(12).HEsareanimportantmeansof enzymesresponsibleforthedetoxificationofCEs, eliminatingestrogen.Oxidationoccursviamajor including2-CEand4-CEby O-methylationandis pathways,oneofwhichinvolvesC-2ofestradiol, polymorphicinthehumanpopulationwith22%ofa resultingintheformationofthe2-HEand4-HE,whereas Turkishpopulationbeinghomozygousforalowactivity theotherinvolvesC-16,resultingintheformationof alleleoftheenzyme(18,19).ThelevelofCOMTactivity 16α-HE.TheseproductsareabletobindtoDNA, iscontrolledbyaDNAexonicpolymorphismatposition creatingadductsandsubsequentlycausinggene 108and158oftheSoluble( S-COMT)andMembrane- mutations.Thus,increasedformationof4-HEand16 α- bound( MB-COMT)formoftheenzyme,respectively. HEhasbeenassociatedwithanelevatedriskofbreast ReducedCOMTactivitymightincreasetheriskofbreast cancer(9).Todate,atleastfourpolymorphismshave cancer,secondarytoaccumulationofCE,whichcauses beendescribedinthehuman CYP1A1 gene.Twoof oxidativeDNAdamage.Inaddition,2-CEand4-CEmay these,m1(abasesubsitutioninnoncodingregion)and beoxidizedtoCEquinones,whichreactwithDNAto m2 (apointmutationincodon462ofexon7,leadingto formadduct.Theseadducts,especiallyCE-3,4-quinones aaminoacidsubsitution)areassociatedwithincreased derivedfrom4-CE,cancausedepurinationleaving breastcancerrisk(13,14). apurinesites,whichisthemajortypeofgeneticdamage Mutationsandpolymorphismshavebothbeen
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