MEK5-Erk5 in breast cancer resistance

MEK5-Erk5 在乳腺癌抵抗中的作用

• 批准号: 8260576
• 负责人: Matthew E. Burow
• 金额: $ 30.1万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260576
• 关键词: AKT3 gene; Adjuvant; Aggressive behavior; Aromatase Inhibitors; Biological; Breast Cancer Cell; Breast Carcinoma; CREB1 gene; Cell Survival; Cell model; Data; Drug resistance; Endocrine; Estrogen Antagonists; Estrogens; Exhibits; Gene Expression; Gene Expression Profiling; Genes; Goals; Hormones; In Vitro; Link; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Microarray Analysis; Mitogen-Activated Protein Kinases; Molecular; Molecular Target; Morphology; Neoplasm Metastasis; Pathway Analysis; Pathway interactions; Pattern; Phenotype; Phosphotransferases; Play; Process; Proto-Oncogene Proteins c-akt; Publishing; Regulation; Research; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; System; Tamoxifen; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Transcription Factor AP-1; Transcriptional Regulation; Up-Regulation; Xenograft procedure; base; cancer cell; design; drug development; effective therapy; epithelial to mesenchymal transition; gene function; hormone therapy; in vivo; insight; malignant breast neoplasm; malignant phenotype; molecular marker; mouse model; novel; prognostic indicator; prospective; resistance mechanism; response; slug; small hairpin RNA; therapeutic development; tool; transcription factor; tumor; tumor progression; tumorigenesis

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.

概括 对治疗药物产生耐药性是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传导和基因的变化 促进生存和增殖的表达，最终导致更恶性的进展 表型。本研究的长期目标是了解 MEK5-Erk5 信号传导的作用 乳腺癌肿瘤发生和耐药途径，旨在开发靶向药物 治疗干预策略。利用基因表达谱分析和细胞信号检查，我们 已确定并暗示 MEK5-Erk5 通路是获得性耐药的关键组成部分 协调乳腺癌细胞中 EMT 和 ER¿ 阴性表型的获得。我们的初步数据 进一步表明 MEK5 信号传导通过下游转录因子发挥作用来介导 EMT 调节因子（SLUG、ZEB1、ZEB2）和 AKT3 的表达。根据这些信息我们假设 MEK5-Erk5 信号通路的上调可诱导上皮间质转化， ER¿ 表达，并驱动乳腺癌细胞向激素非依赖性和治疗性进展 耐药表型。拟议的具体目标旨在确立 MEK5 的作用，定义 在体外和体内发生耐药表型进展的具体机制。目标#1： 检验 MEK5 介导的乳腺癌肿瘤发生需要 Erk5 信号传导的假设，以及 治疗抵抗。目标#2：检验 MEK5-Erk5 信号传导在进展中发挥作用的假设 通过破坏 ER¿ 信号轴实现内分泌独立和耐药。目标#3：测试 假设 MEK5-Erk5 信号轴促进上皮间质转化，ER¿ 阴性 和侵袭表型。在此提案中，我们希望定义并链接 MEK5-Erk5 信令的直接角色 途径在治疗耐药性的发展和侵袭性表型的促进中发挥作用 癌细胞。这种连接的建立将 MEK5-Erk5 通路定义为潜在的分子 标记物可用作治疗反应的预后指标和前瞻性分子靶标 用于药理学药物开发。