IndianJEndocrinolMetab.Dec201216(Suppl2):S195S198.

PMCID:PMC3603025

doi:10.4103/22308210.104038

Prolactinandcancer:Hastheorphanfinallyfoundahome?
BipinKumarSethi,G.V.Chanukya,andV.SriNagesh
DepartmentofEndocrinologyandMetabolism,CareHospitals,BanjaraHills,RoadNumber1,Hyderabad500034,Andhra,Pradesh,India
CorrespondingAuthor:BipinKumarSethiDepartmentofEndocrinologyandMetabolism,CareHospitals,BanjaraHills,RoadNumber1,Hyderabad
500034,Andhra,Pradesh,India.Email:bipinkumarsethi@yahoo.co.uk
Copyright:IndianJournalofEndocrinologyandMetabolism
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Abstract

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Prolactinhas,forlong,beenassociatedwithgalactorrheaandinfertilityinwomenwhileitsroleinmenislargely
unknown.Recently,expressionofprolactininvariousothertissueslikethebreast,prostate,decidua,andthebrain
hasbeenrecognized.Thishasledtoevaluationofparacrineandautocrineactionsofprolactinatthesetissuesanda
possibleroleindevelopmentofvariouscancers.IncreasedexpressionofPRLreceptorshasalsobeenimplicatedin
carcinogenesis.Breastcancerhasthestrongestassociationwithincreasedprolactinandprolactinreceptorlevels.
Prostatecanceralsohasreportedsignificantassociation,whiletheroleofprolactinincolorectal,gynecological,
laryngeal,andhepatocellularcancersismoretenuous.Prolactin/prolactinreceptorpathwayhasalsobeen
implicatedindevelopmentofresistancetochemotherapy.Thus,theeffectsofthispathwayincarcinogenesisseem
widespread.Atthesametime,theyalsoofferanexcitingnewapproachtohormonalmanipulationofcancers,
especiallythetreatmentresistantcancers.
Keywords:Prolactin,cancer,carcinogenesis
INTRODUCTION

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Prolactin(PRL),thepeptidehormonesecretedbytheanteriorpituitarygland,has,forlong,remainedrestrictedto
thefieldoflactationandinfertility.Whileafewstudiesrecentlyhavedealtwiththeuseofprolactinin
differentiatingtrueandpseudoseizures,themultipleeffectsofthishormonehavelargelyremainedunknown.The
connectionbetweenprolactinandcancerhasbeensuspectedformanyyears,butneverconclusivelyproven.The
similarityofprolactinwithgrowthhormoneanditsactionsthroughthegrowthpromotingJAK/STATpathway
suggestitstumorpromotingeffects.RecentresearchhasunderlinedtheroleofPRLandPRLreceptor(PRLR)
mostimportantlyinbreastandprostatecancers,butalsoinavarietyofothercancers.Thisreviewarticlehasbeen
designedtopresentanoverviewoftherecentunderstandingregardingroleofPRLincancerandnewmodalitiesof
cancertherapybasedonthePRLpathway.
Breastcancer

Breastcancerisoneofthecommonestcancersinwomen,withoveronemillioncasesreportedworldwide,making
up25%ofallcancersinwomen.Inspiteoftheavailabilityofadvancedtreatmentslikesurgery,chemotherapy,and
radiotherapy,thediseasecontinuestotakeitstoll,withahighincidenceoftreatmentfailureduetotumorresistance,

bothintrinsicandacquired.Thishaspromptedthesearchforfactorscausingitandalsothemeanstocounteractit,
andprolactinisonesuchcandidate.Theconceptofprolactinasafactorinmammarycancerisnotnew.Itwas
initiallysuggestedoverthreedecadesago,basedondataobtainedfrommurinemodels.Foralongtime,thisanimal
datacouldnotbeextrapolatedtohumansduetovarietyofreasons:(i)mostofthesestudiesinvolvedonlyafew
subjects,(ii)aconceptoflocalproductionofprolactininbreasttissuedidnotexist,(iii)mostofthestudies,which
usedbromocriptinetoreduceserumprolactinlevels,didnotleadtosuccessfultreatment,and(iv)mostofthese
studiesdidnotreachspecificconclusionsabouttherelationbetweenprolactinandbreastcancer.However,thehigh
incidenceoftreatmentfailureandanumberofrecentepidemiologicalstudieshaveagainshiftedthefocusbackon
toprolactin.Theserecentstudieshavebroughttofore,afewcriticalconceptsregardingtheroleofprolactin(PRL)
inbreastcancer.(i)EvenhighnormalcirculatinglevelsofPRLincreasebreastcancerrisk.(ii)Locallyproduced
prolactinactsasanautocrine/paracrinefactorinbreastcancerevolution.(iii)Acausalrelationshipbetween
prolactinreceptorexpressionandbreastcancerhasalsobeenrecognized.[1]
TheexactmechanismbywhichhighnormalcirculatinglevelsofPRLleadstoincreasedbreastcancerriskisnot
exactlyknown.PRLmaypromotebreastcancerviatheJAK2/STAT5signalingpathwayandmayalsoincrease
thesurvivalofbreastcancercellsbystimulatinggenerationofnewcancercellsanddecreasingcelldeath.PRL
couldalsoincreasecellmotilityandpromotecancerspread.PRLhasalsobeenimplicatedincausingresistanceto
cytotoxicdrugslikecisplatinanddrugslikepaclitaxel,whichactoncellularmicrotubules.
Circulatingprolactinproducedbythepituitaryisnottheonlyprolactinavailabletotissues.Manyorganslikethe
mammarygland,prostate,brain,deciduas,andskinalsoexpressPRL.Thisextrapituitaryprolactinprobablyis
involvedindevelopmentofbreasttissue,dermatologicalbioregulation,andperceptionofpain.Whileextra
pituitarysecretionhasalsobeenreportedinanimalmodels,itisassumedtobemuchmorecommoninhumansand
isdopamineandPOU1F1independent.AspecificregulatoroflocalPRLproductionhasstillnotbeenidentified,
eventhoughinsulin,progesterone,andtransforminggrowthfactorhavebeenproposedasregulators.Inthe
breast,PRLisproducedinboththestromalandepithelialcompartments.Further,whileverylittleprolactinis
producedlocally,itisveryimportantfortumorformationduetolocalavailability.
AfewstudieshavealsofoundthatbreasttumorsalsoexpresshigherlevelsofthePRLreceptor(PRLR)when
comparedtoadjacenthealthytissue.[2,3]Evenlowlevelsofprolactinreceptorexpressionareadequatetomediate
actionsofPRLinbreastcancercelllines.Afamilyofprolactinreceptor(PRLr)isoforms,numberingsix,mediates
theeffectsofPRLinhumantissue.Thesesixisoformsarevariablyexpressedinnormaltissuesandmalignant
tissues.PRLRtriggeredsignalingcascadeshavealsobeenimplicatedinbenignbreasttumors.Astudyby
Plotnikovetal.[4]foundthatimpairedturnoveroftheprolactinreceptorinbreastcancercellsresultsinaccelerated
proliferationandincreasedinvasivegrowth.Conversely,antagonismoftheprolactinreceptorresultedinreduction
ofclonogeniccapacityofbreastcancercellsandpotentiatedtheactionofcytotoxicanticancerdrugs.[5]Thishas
veryimportantimplicationsinchemotherapyofbreastcancer,especiallytheresistanttypes.Thelocalproductionof
prolactincannotbecontrolledbyconventionaldopamineagoniststhatactatthepituitarylevel.Thisfailureof
bromocriptine(themostcommonlyuseddopamineagonistincancerstudies)toreducelocalPRLlevelsresultedin
thefailureofthisdrugincancerstudies.Thishighlightstheneedtodevelopaspecialcategoryoftherapeuticagents
targetedatreducingtheactionofendogenousPRLbyblockingthePRLreceptor.ThehumanPRLRantagonist
G129RhPRL,whichstericallyhindersthesequentialdimerizationandsubsequentactivationofthePRLR,causes
apoptosisofbothestrogenreceptorpositiveandestrogenreceptornegativebreastcancercelllines.Inthestudyby
Howelletal.,[5]thepureprolactinreceptorantagonist19significantlyaugmentedthecytotoxiceffectsof
doxorubicinandpaclitaxelinvitro.Thistherapyalsoinhibitedthecolonyformingefficiencyofcelllinesand
primarycancers.Autocrineprolactininbreastcancercelllinescanalsobeantagonizedbyprolactinneutralizing
antibodies.[6]Mostofthestudiesonantibodieshavebeeninvitro,inwhichtheseneutralizingantibodieshavebeen
showntoinhibitMCF7andT47Dcocellgrowthandtoincreasecellapoptosis.[7]Thus,thesestudiessuggestthat
ajudiciouscombinationofcytotoxicagents,PRLRantagonists/neutralizingantibodiescouldprovideanewformof

therapyforresistantbreastcancers.Atthegeneticlevel,constructionofaPRLRsinglenucleotidepolymorphism
riskprofileforaffectedpatientscouldenablepersonalizedtreatmentstrategies.
Interactionsbetweenestrogenandprolactinsystems

Recentresearchhasindicatedsignificantinteractionbetweenestrogenandprolactinsystems.Estrogenstimulates
prolactinsecretionandcanalsoupregulatehumanprolactinreceptorgeneexpressionandstimulategrowthof
tumorigenesis.[8]Prolactinhasbeenshowntoexertsomeofitseffectsonmammarytumorcellsviatheestrogen
receptor.Antiestrogensliketamoxifenhavealsobeenfoundtoblocktheprolactinreceptors.Thiscouldrepresent
anotherpathwayofcancertherapy,discretefromtheantiestrogeniceffectsofthesedrugs.Interestingly,
hyperprolactinemiaresultsinhypogonadism,suppressestheovarianreproductivecycle,andreducesestrogen.
Thus,theinteractionsbetweenprolactinandestrogenpathwaysarecomplex,andcarefulstudiesareneededto
formulatetreatmentstrategies.
PROSTATECANCER

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Prostatecancerispresentlythemostfrequentlydiagnosedcancerandrepresentsthesecondmostcommoncauseof
deathfromcancerinmen.PRLhasanimportantroleinthedevelopmentofprostategland.In1955,Grayhack[9]
discoveredthatwhenprolactinwasinhibitedinratsduringembryonicdevelopment,only80%oftheprostatewas
developed,whichshowsthatprolactinisimportantindifferentiationanddevelopmentoftheprostate.Thereisalso
significantevidenceoftheexistenceofprolactin'sparacrineandautocrineactions.Themainstayoftreatmentof
prostatecancerincludesradicalprostatectomy,radiation,andandrogendeprivationtherapy.However,justlikein
breastcancer,resistancetohormonetherapyhasalsobeennotedinprostatecancer.Also,prostatecanceroften
metastasizestothebone,whichmakestreatmentevenmoredifficult.Epidemiologicalstudiesexploringa
correlationbetweenserumPRLlevelsandprostatecancerincidenceorseverityhavebeenequivocal.Both
malignantandhealthyprostatesproducePRL.ThePRLpositivetissuesshowagoodcorrelationwithactivated
Stat5andahighGleasonscore.ProstaticfluidsfrompatientswithcanceralsohavehigherPRLlevelsthan
controls,whichalsolendsupporttotheexistenceofprostatederivedPRL.Mostoftheeffectsofprolactinon
prostatecancercellsaresimilartothoseonbreastcancercells.Invitro,prolactininducesproliferationand
antagonizesapoptosisinprostateorgancultureandinsometumorcelllines.Inhumans,receptorsforprolactinare
expressedintheprostate,andthisexpressionisparticularlyelevatedinprostatecancerandcarcinomainsitu.While
hypogonadismcausedbyhyperprolactinemiacouldhavearoleinreductionofprostatecancer,asreportedina
study,[10]thebulkofevidenceseemstosuggestthatupregulationofPRLRandlocalproductionofPRLin
prostatecouldbeimportantinincreasedriskofprostatecancerandtreatmentresistance.
COLORECTAL CANCER

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Colorectalcanceristhethirdhighestcauseofcancermortalityworldwide.CEAisthemostcommonmarker
utilizedforthedetectionandfollowupofcolorectalcancer.However,astudybySoroushetal.[11]compared
serumPRLandCEAlevelof47patientsandfoundthatserumPRLandCEAlevelswereincreasedinpatients
withcolorectalcancer,butthegreaterportionofthepatientshadanincreasedlevelofPRLcomparedwithelevated
levelofCEA.TheyalsofoundnocorrelationbetweentheplasmaPRLconcentrationandthestageofthetumor.
TheyconcludedthatinviewofthehighcostofCEA,prolactincouldbeusedasatumormarkerforcolorectal
cancer.SimilarresultshavebeenfoundinastudybyBhatavdekar.[12]However,evidenceabouttheroleof
prolactinincolorectalcancerhasbeenmixed,anditsroleincolorectalcancerremainscontentious.
HEPATOCELLULARCARCINOMA

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Hepatocellularcarcinoma(HCC)accountsformorethan6lakhnewcasesperyearworldwide.Despiteseveral
treatmentmodalities,thelongtermsurvivalrateremainsunsatisfactory,principallyduetohighratesofrecurrence
andmetastasisevenaftertreatment.Increasedcirculatingprolactinlevels,highpJAK2expression,andgeneration

oflivercancercellsthroughPRLR/JAK2signalinghaveallbeenproposedasmechanismsthatcouldcontributeto
thedevelopmentofHCC.AstudybyYehetal.[13]demonstratedsignificantlyhigherserumlevelsofprolactinin
peoplewithHCC,andthissignificantrelationshipexistedirrespectiveofgender,age,orBMI.Thesefindingshave
significantimplicationsinthedetectionandtherapyofHCC,ifproven.Hence,largerstudies,whichcanprovethe
roleofPRLinactivationofJAK2andexcludetheroleofothercytokinesandgrowthfactorsintheJAK2
activationpathway,needtobedesignedimmediately.
GYNECOLOGICAL CANCERS

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ElevatedlevelsofserumPRLinovarianandendometrialcancershavebeenreported,indicatingapotentialrolefor
PRLingynecologicalcancers.PRLpossiblypromotestumorigenesisbyactivatingRasoncogene,andthuscould
leadtocellswithmutationsintumorsuppressorgenesturningmalignant.AstudybyLevinaetal.[14]found
dramaticallyincreasedexpressionofPRLreceptorinovarianandendometrialtumorsaswellasinendometrial
hyperplasia,signifyingtheimportanceofPRLsignalinginmalignantandpremalignantconditions.PRLmRNA
wasexpressedinovarianandendometrialtumors,indicatingthepresenceofanautocrineloop.SerumPRLlevels
werealsosignificantlyelevatedinwomenwithastrongfamilyhistoryofovariancancer,andthisPRLrisecould
notbeattributedtostress.
MALIGNANT LARYNGEAL TUMORS

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Laryngealcancer(LC)isresponsibleforapproximately159,000newcasesand90,000mortalitieseveryyear.The
mechanismsunderlyingtheproliferationofthisformofcancerarenotyetfullyunderstood.Arecentstudyby
GonzlezLucanoetal.[15]foundincreasedexpressionofdifferentisoformsofPRLRinLCincomparisonwith
recurrentrespiratorypapillomatosis.ThissuggestedapossibleroleofPRL/PRLRinthedevelopmentofLC.They
concludedthatPRLRmightbeusefulasatargetforfurtherinvestigationsinlaryngealtissues.
ALL CAUSEMORTALITY

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InviewofthewidespreadexpressionofPRLinvarioustissuesandtheemergingroleofprolactinincausing
multiplecancers,astudywasdevisedbyBerinderetal.[10]toassesstheoverallrelativeriskofcancerandriskof
somespecificapriorispecifiedcancerformsinacohortof969womenandmenwithhyperprolactinemia.Their
resultsweredifferentfromthemajorityofprolactinandcancerstudies,andtheyreportedahigherincidenceof
uppergastrointestinalcancerinbothmalesandfemalesandhematopoieticcancerinfemales.Riskofbreastcancer
wasnotincreasedinwomen,andtherewasareducedriskofprostatecancerinmen.Anincreasedoverallcancer
riskwasfoundinhyperprolactinemiapatients.
ThelastwordontheroleofPRLincausingcancerandonitsreceptorconferringresistancetochemotherapeutic
agentsisyettobewritten.Themorethenumberofcancersaddedtothelist,themoreisthestorygettingcuriouser
andcuriouser.Clearly,anassociationhasbeendemonstrated,butwhetherthatisacauseandeffectrelationshipis
yettobeestablished.ThemodestPRLelevationscouldbeoflocalorigin.Higherlevelsthatareobtainedin
prolactinomasusuallycausehypogonadism,somethingthatchemotherapiesforbreastandprostatecancertreatment
aimat,andhencethishighserumPRLcertainlycannotbeblamedforcausingthesecancers.
Footnotes

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SourceofSupport:Nil
ConflictofInterest:Nonedeclared.

REFERENCES
1.BernichteinS,TouraineP,GoffinV.Newconceptsinprolactinbiology.JEndocrinol.2010206:111.
[PubMed]

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2.ReynoldsC,MontoneKT,PowellCM,TomaszewskiJE,ClevengerCV.Expressionofprolactinandits
receptorinhumanbreastcarcinoma.Endocrinology.1997138:555560.[PubMed]
3.TranThanhD,ArnesonNC,PintilieM,DeliallisiA,WarrenKS,BaneA,etal.Amplificationoftheprolactin
receptorgeneinmammarylobularneoplasia.BreastCancerResTreat.2011128:3140.[PubMed]
4.PlotnikovA.Impairedturnoverofprolactinreceptorcontributestotransformationofhumanbreastcells.Cancer
Res.200969:316572.[PMCfreearticle][PubMed]
5.HowellSJ,AndersonE,HunterT,FarnieG,ClarkeRB.Prolactinreceptorantagonismreducestheclonogenic
capacityofbreastcancercellsandpotentiatesdoxorubicinandpaclitaxelcytotoxicity.BreastCancerRes.
200810:R68.[PMCfreearticle][PubMed]
6.ChenWY,RamamoorthyP,ChenN,SticcaR,WagnerTE.Ahumanprolactinantagonist,hPRLG129R,
inhibitsbreastcancercellproliferationthroughinductionofapoptosis.ClinCancerRes.19995:358393.
[PubMed]
7.PerksCM,KeithAJ,GoodhewKL,SavagePB,WintersZE,HollyJM.Prolactinactsasapotentsurvivalfactor
forhumanbreastcancercelllines.BrJCancer.200491:30511.[PMCfreearticle][PubMed]
8.DongJ,TsaiMorrisCH,DufauML.Anovelestradiol/estrogenreceptoradependenttranscriptionalmechanism
controlsexpressionofthehumanprolactinreceptor.JBiolChem.2006281:1882536.[PubMed]
9.GrayhackJ,BunceP,KearnsJ,ScottW.Influenceofthepituitaryonprostaticresponsetoandrogenintherat.
BullJohnsHopkinsHosp.195596:15463.[PubMed]
10.BerinderK,AkreO,GranathF,HultingAL.Cancerriskinhyperprolactinemiapatients:Apopulationbased
cohortstudy.EurJEndocrinol.2011165:20915.[PubMed]
11.SoroushAR,ZadehHM,MoemeniM,ShakibaB,ElmiS.Plasmaprolactininpatientswithcolorectalcancer.
BMCCancer.20044:97.[PMCfreearticle][PubMed]
12.BhatavdekarJM,PatelDD,ChikhlikarPR,ShahNG,VoraHH,GhoshN,etal.Ectopicproductionof
prolactinbycolorectaladenocarcinoma.DisColonRectum.200144:11927.[PubMed]
13.YehYT,LeeKT,TsaiCJ,ChenYJ,WangSN.ProlactinPromotesHepatocellularCarcinomathroughJanus
Kinase2.WorldJSurg.201236:112835.[PubMed]
14.LevinaVV,NolenB,SuY,GodwinAK,FishmanD,LiuJ,etal.Biologicalsignificanceofprolactinin
gynecologiccancers.CancerRes.200969:522633.[PMCfreearticle][PubMed]
15.GonzlezLucanoLR,MuozValleJF,AscencioCedilloR,DomnguezRosalesJA,LpezRincnG,Del
ToroArreolaS,etal.Increasedexpressionoftheprolactinreceptorisassociatedwithmalignantlaryngealtumors.
ExpTherMed.20123:6037.[PMCfreearticle][PubMed]
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