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

超出所提供的空间。乳腺癌是美国最常见的癌症之一，每年有超过18万的新病例被诊断出来。大约一半的乳腺癌患者死于这种疾病，因为转移性乳腺癌仍然是一种通常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武器。然而，癌细胞经常对这些药物产生耐药性。我们已经确定Ras/Raf/MEWERK信号转导级联的激活将导致MCF-7乳腺癌细胞在化疗药物多柔比星和紫杉醇存在下的增殖能力增加。Raf激活的后果可能包括药物转运因子dr-1、抗凋亡基因cl-2和自生长因子（如双调节因子）的表达增加，这些因子与HER2生长因子受体结合，与乳腺癌的病因有关。在拟议的研究中，我们将确定通过Ras/Raf/MEWERK信号转导途径诱导mdr-1、bcl-2和自生长因子表达是否对诱导乳腺癌耐药至关重要，以及这种情况发生的机制。为了实现这些目标，提出了三个具体目标：目标1。为了确定Ras/Raf/MEWERK通路调控mdr-1、bcl-2和自生长因子的机制，以及它们的诱导表达是否与乳腺癌耐药有关，目的2。目的探讨Ras/Raf/MEWERK和Ras/PI3K/PTEN/PDK/Akt通路相互作用和调控dr-1、bcl-2和乳腺癌耐药的机制。目标3。确定Ras/Raf/MEWERK通路影响乳腺癌细胞氧化还原状态以调节其对化疗药物敏感性的机制。通过这些研究，将有更多的信息可用于联合使用药物治疗乳腺癌和其他癌症患者，这些药物抑制信号转导和抗凋亡途径导致耐药性。网站性能 ======================================== 节结束 ===========================================

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===========================================