Ras/Raf & PI3K/Akt Induced Breast Cancer Drug Resistance

$294,304R01FY2007CANIH

East Carolina University, Greenville NC

Investigators

Linked publications & trials

Paper 21881167 Paper 21869603 Paper 21730367 Paper 20671809 Paper 20436278 Paper 20436269 Paper 20372086 Paper 19895837 Paper 19351820 Paper 19342873 Paper 19010914 Paper 18838868 Paper 18829542 Paper 18800146 Paper 18594202 Paper 18577685 Paper 18423407 Paper 18418057 Paper 18332865 Paper 18256541 Paper 18059157 Paper 17651485 Paper 17482503 Paper 17382374 Paper 17361225 Paper 17224638 Paper 17172846 Paper 17126425 Paper 16987033 Paper 16987031 Paper 16987028 Paper 16987027 Paper 16855386 Paper 16687919 Paper 16675657 Paper 16642049 Paper 16410717 Paper 16322681 Paper 16267021 Paper 16211230 Paper 16185155 Paper 16177564 Paper 16096377 Paper 16096376 Paper 16083343 Paper 15970693 Paper 15970551 Paper 15958590 Paper 15917660 Paper 15917193 Paper 15912514 Paper 15908804 Paper 15899832 Paper 15870880 Paper 15701973 Paper 15584861 Paper 15548710 Paper 15542692 Paper 15496972 Paper 15467757 Paper 15294913 Paper 15254746 Paper 15254407 Paper 15122343 Paper 15004527 Paper 14752274 Paper 14726697 Paper 14712088 Paper 14688475 Paper 14562120 Paper 14508104 Paper 12835716 Paper 12631622

Abstract

Breastcanceris among the most commonformsof cancerwithover 180,000 newcases diagnosed inthe USA each year. Approximatelyhalf of all breastcancerpatientsdie from the diseasebecause metastaticbreastcancer remainsa generallyincurableandfatal disease.Cytotoxicdrugtreatment is an importantweapon againstcancer.However, cancerouscellsfrequentlydevelopdrug resistanceto these agents.We have determinedthat activationof the Ras/Raf/MEWERK signal transductioncascadewill lead to an increasedabilityof MCF-7 breastcancercellsto proliferatein the presenceof the chemotherapeuticdrugsdoxorubicinand paclitaxel.Consequencesof Raf activationmay includeincreasedexpressionof the drugtransportermdr-1, the anti-apoptoticbcl-2 gene, and autocrinegrowthfactorssuchas suchas amphiregulinwhichbindthe HER2 growth factor receptorimplicatedin the etiologyof breastcancer.In the proposedstudies,we will determinewhether inductionof mdr-1, bcl-2and autocrinegrowthfactor expressionbythe Ras/Raf/MEWERK signaltransductionpathwayis essentialfor inductionof breastcancerdrug resistanceandthe mechanismsby whichthisoccurs.To achievetheseobjectives,threespecific aims have been proposed:Aim 1. To determinemechanismsby whichthe Ras/Raf/MEWERK pathwayregulatesmdr-1, bcl-2, and autocrinegrowthfactors andwhethertheirinducedexpression is requiredfor breastcancerdrugresistance,Aim 2. To determinemechanismsby whichthe Ras/Raf/MEWERK and Ras/PI3K/PTEN/PDK/Akt pathwaysinteractand regulatemdr-1, bcl-2and breastcancerdrugresistance.Aim 3. To determinemechanismsbywhich Ras/Raf/MEWERK pathwayinfluencesthe redoxstatusof breastcancercellsto modulatetheirsensitivityto chemotherapeuticdrugs.Throughthese studies,moreinformationwillbe availableto treatbreast andothercancerpatientswithcombinationsof drugs,whichinhibitsignaltransductionand anti-apoptoticpathwaysleadingtodrug resistance.

View original record on NIH RePORTER →