02 Rakesh Kumar. Molecular Pathways and Targets of Breast Cancer

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1、MolecularPathwaysandTargetsofBreastCancerRakeshKumar,Ph.D.ProfessorofBiochemistryandMolecularMedicineGeorgeWashingtonUniversityHumanBreastHumanBreastCarcinomaCarcinomaCarcinoma::BiologicSubtypesBiologicSubtypesHumanBreastCarcinomasGrowthFactorsERSignalingEstrogenEstrogenCancerProgres

2、sionandTherapeuticMajoropenquestions-Resistance•Moleculardeterminantsoftherapeuticresistance•MechanismofERaction:emergingroleofco-regulators•Roleofnone-genomicestrogensignalinganditscross-talkwithGF•SearchfornewHER2targetsandroleinbreastcancerprogressionGrowthFactorReceptorsinGrowth

3、RegulationinCancerCellsGrowthfactorsStromaEndothelialcellsBonemarrowTGFEGFParacinestimulationTGFAutocrinestimulationGrowthfactorsGrowthFactorSignalstheCellCycleControlSystemGrowthfactorPlasmamembraneReceptorG1checkpointproteinDrugTargetsRelayproteinsGSSignaling1ControlpathwaySystem

4、MG2GrowthFactorSignalinginCancerCellsASimplifiedModelGFReceptorsTherapeuticPTargetsSignalingCascadesEffectorProteinsExtra-nuclearfunctionsGeneExpressionTargetProteinsModulationofNormalandPathologicStatesTargetingEGFRandHER2byBlockingAbsFGTC225HerceptinEGFREGFRHER2HER3/4XXSignalingCa

5、scadesBiologicalResponsesGrowthStimulationApoptosisCellCycleProgressionChemosensitization?DNA-Repair?ASimplifiedModelofERActionE2Anti-estrogensHRG/HER2ERE2CoAE2MTA1CoRERHATCoRERHDACERHDACGeneExpressionGeneRepressionER-positiveER-negativeCellularEffectsofERTargetGeneProductsCoregula

6、torsintheActionofEstrogenReceptorCoregulatorsintheActionofEstrogenReceptorOncogene,Cytoskeleton,andCytoplasmickinasesEstrogenHATERPCoactivatorsInsensitivetoSERMSERMHRG/HER2ERAnti-estrogensEREHistoneNCoRHDACdeacetylationCoREREREREActivationRepressionGeneProductsER-phenotypes••Levelsa

7、ndactivationstatusofcytoplasmickinases,Levelsandactivationstatusofcytoplasmickinases,coactivators,andcorepressorscoactivators,andcorepressors--asbiomarkersasbiomarkers???EstrogenReceptorSignalingRTKERCoAERERNon-genomicHormoneResponsesE2IndependenceERCoRCoAE2CoRERCoATranscriptionEffe

8、ctsSignaling