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1、Page1of47AcceptedPreprintfirstpostedon30August2012asManuscriptERC-12-020312345678Thecellularandmolecularmechanismsbywhichinsulininfluencesbreastcancer9riskandprogression1011DavidPRoseandLindaVona-Davis1213DepartmentofSurgeryandBreastCancerResearchProgram,Ma
2、ryBabbRandolphCancerCenter,14WestVirginiaUniversity,POBox9238,Morgantown,WestVirginia26506,USA1516(Requestforoffprintsshouldbeaddressedtolvdavis@hsc.wvu.edu)1718ShortTitle:Insulinandbreastcancer1920Keywords:breastcancer;insulin;adipokines;leptin;adiponectin
3、;paracrine;angiogenesis2122RevisionstoMs./Ref.No:ERC-12-0203232425261Copyright?2012bytheSocietyforEndocrinology.Page2of4727Abstract28Epidemiologicalstudieshaverelatedhyperinsulinemiaandtype2diabetestoanincreasedbreastcancer29risk,anaggressiveandmetastaticph
4、enotype,andapoorprognosis.Furthermore,diabeticretinopathy30arisesfrompathologicalangiogenesis,whichisalsoessentialforbreastcancergrowthandmetastasis.31Insulinstimulatestheproliferationofsomehumanbreastcancercelllinesinvitrobymechanismsthat32utilizeboththeph
5、osphatidylinositol-3kinaseandMAPkinase/Aktsignalingpathways;itisalsoacell33survival(anti-apoptotic)agent,andenhancestumorcellmigrationandinvasivecapacity.34Hyperinsulinemiaaffectsbreastcancercellsviatheendocrinesystem,butexperimentalstudiessuggest35theimpor
6、tanceofparacrinemechanismsoperatingbytheeffectsofinsulinonthesecretionof36adipokinesfromtumor-associatedadiposetissue.Insuchasystem,oneadipokine,leptin,has37stimulatoryparacrineeffectsonbreastcancercellproliferationandsurvival,whileasecond,38adiponectin,isi
7、nhibitory.Leptin,vascularendothelialgrowthfactor,anotherinsulin-regulated39adipokine,andinsulinitselfalsostimulateangiogenesis.Insulinhascomplexinteractionswith40estrogens:itinducesadiposestromalcellaromataseandtumorcellsexsteroidhormonereceptor41expression
8、,andsuppressessexhormone-bindingglobulin,whichmayenhanceestrogensynthesisand42bioactivitywithconsequentpromotionofestrogen-dependentbreastcancer.Alloftheseactions43influencethelaterstepsinbreastcancerd
