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

乳腺癌是最常见的癌症之一， 美国每年。大约一半的乳腺癌患者死于这种疾病， 转移性乳腺癌是一种通常无法治愈和致命的疾病。 是一种重要的抗癌药物。然而， 对这些药剂的耐药性。我们已经确定Ras/Raf/MEWERK信号的激活 转导级联将导致MCF-7乳腺癌细胞增殖能力的增加， 化疗药物阿霉素和紫杉醇的存在。Raf的后果 激活可能包括药物转运蛋白mdr-1，抗肿瘤细胞凋亡基因bcl-2 基因和自分泌生长因子，如结合HER2生长的双调蛋白， 因子受体与乳腺癌的病因学有关。在拟议的研究中，我们将 检测是否诱导mdr-1、bcl-2和自分泌生长因子表达。 Ras/Raf/MEWERK信号转导通路在乳腺癌药物诱导中的作用 为了实现这些目标，我们提出了三个具体的目标， 提出了以下目标：目标1。确定Ras/Raf/MEWERK的机制 调节smdr-1、bcl-2和自分泌生长因子的途径以及它们是否诱导表达 是乳腺癌耐药的必要条件，目标2。为了确定 Ras/Raf/MEWERK和Ras/PI3K/PTEN/PDK/Akt通路相互作用，调控dr-1、bcl-2和 乳腺癌耐药。目标3。确定Ras/Raf/MEWERK的机制 影响乳腺癌细胞氧化还原状态的途径 通过这些研究，更多的信息将可用于治疗乳腺癌 以及其他癌症患者与药物的组合，这阻碍了信号转导， 抗肿瘤途径导致耐药性。

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.