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

超出所提供的空间。乳腺癌是最常见的癌症之一，在美国每年诊断出超过18万例新病例。大约一半的乳腺癌患者死于这种疾病，因为转移性乳腺癌通常是无法治愈和致命的疾病。细胞毒性药物治疗是对抗癌症的重要手段。然而，我们已经确定Ras/Raf/MEWERK信号转导级联的激活将导致MCF-7细胞增殖能力的增加。在化疗药物阿霉素和紫杉醇的存在下，Raf激活的结果可能包括：药物转运蛋白mdr-1、抗肿瘤基因bcl-2和自分泌生长因子如结合HER 2生长因子受体的双调蛋白与乳腺癌的发病有关，在本研究中，我们将确定通过Ras/Raf/MEWERK信号转导途径诱导mdr-1、bcl-2和自分泌生长因子的表达是否是诱导乳腺癌耐药的必要条件，以及其发生的机制。确定Ras/Raf/MEWERK途径调节smdr-1、bcl-2和自分泌生长因子的机制，以及它们的诱导表达是否是乳腺癌耐药所必需的，目的2。探讨Ras/Raf/MEWERK和Ras/PI 3 K/PTEN/PDK/Akt通路相互作用调节dr-1、bcl-2基因表达与乳腺癌耐药的机制。本研究旨在明确Ras/Raf/MEWERK通路影响乳腺癌细胞氧化还原状态从而调节其对化疗药物敏感性的机制，为乳腺癌及其他癌症患者联合用药治疗提供更多信息，这些信息包括信号转导和抗肿瘤通路导致的耐药。性能现场=

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================