MEK5-Erk5 in breast cancer resistance

总结 对治疗剂的耐药性的发展代表了有效治疗的重大障碍 癌症。在分子水平上，这种耐药性的特征是信号和基因的变化。 促进存活和增殖的表达，最终允许进展到更恶性的肿瘤。 表型这项研究的长期目标是了解MEK 5-Erk 5信号转导的作用， 乳腺癌的肿瘤发生和耐药途径，目标是开发靶向 治疗干预的策略。使用基因表达谱和细胞信号检查， 已经确定并暗示MEK 5-Erk 5途径是获得性抗性的关键组成部分 与乳腺癌细胞中EMT和ER阴性表型的获得相协调。我们的初步数据 进一步表明MEK 5信号通过下游转录因子介导 EMT调节子（SLUG、ZEB 1、ZEB 2）和AKT 3的表达。根据这些信息，我们假设 MEK 5-Erk 5信号通路的上调诱导上皮细胞向间充质细胞转化， ER表达，并推动乳腺癌细胞向非依赖性和治疗性乳腺癌细胞的发展。 抗性表型拟议的具体目标旨在确立MEK 5的作用， 在体外和体内发生向抗性表型进展的特定机制。目标1： 检验ERK 5信号传导是MEK 5介导的乳腺癌肿瘤发生所需的假设， 治疗抵抗目的#2：为了检验MEK 5-Erk 5信号传导在向细胞凋亡的进展中起作用的假设。 内分泌不依赖性和抵抗通过破坏ER信号轴。目标#3：测试 MEK 5-Erk 5信号轴促进上皮细胞向间充质细胞转化的假说，ER阴性 和侵袭性表型。在这个提议中，我们期望定义和链接MEK 5-Erk 5信号的直接作用 途径在治疗耐药性的发展中起作用，并促进侵袭性表型， 癌细胞这种联系的建立将确定MEK 5-Erk 5途径作为潜在的分子生物学途径。 用作治疗反应的预后指标和作为预期分子靶点的标记物 用于药物开发。

SUMMARY The development of resistance to therapeutic agents represents a significant obstacle in the effective treatment of cancer. At the molecular level this drug-resistance is characterized by changes in signaling and gene expression that promote survival and proliferation, ultimately allowing progression to a more malignant phenotype. The long-term objective of this research is to understand the role of the MEK5-Erk5 signaling pathway in the tumorigenesis and resistance of breast carcinoma with the goal of developing targeting strategies for therapeutic intervention. Using gene expression profiling and examination of cell signaling we have identified and implicated the MEK5-Erk5 pathway as a critical component of acquired resistance coordinate to acquisition of an EMT and ER¿-negative phenotype in breast cancer cells. Our preliminary data further suggests that MEK5-signaling functions through downstream transcription factors to mediate expression of EMT regulators (SLUG, ZEB1, ZEB2) and AKT3. Based upon this information we hypothesize that upregulation of MEK5-Erk5 signaling pathway induces the epithelial-to-mesenchymal transition, loss of ER¿ expression, and drives progression of breast cancer cells to a hormone-independent and therapeutically resistant phenotype. The proposed Specific Aims are designed to establish a role for MEK5 defining the specific mechanisms by which progression to a resistant phenotype occurs in vitro and in vivo. Aim#1: To test the hypothesis that Erk5 signaling is required for MEK5 -mediated breast cancer tumorigenesis and therapeutic resistance. Aim#2: To test the hypothesis that MEK5-Erk5 signaling functions in the progression to endocrine-independence and resistance through disruption of the ER¿-signaling axis. Aim#3: To test the hypothesis that the MEK5-Erk5 signaling axis promotes an epithelial-to-mesenchymal transition, ER¿-negative and invasive phenotype. In this proposal we expect to define and link a direct role the MEK5-Erk5 signaling pathway plays in the development of therapeutic resistance, and promotion of an aggressive phenotype in cancer cells. The establishment of this connection would define the MEK5-Erk5 pathway as potential molecular markers to be utilized as a prognostic indicator of therapeutic response and as a prospective molecular target for pharmacological drug development.