MEK5-Erk5 in breast cancer resistance

MEK5-Erk5 在乳腺癌抵抗中的作用

• 批准号: 8463129
• 负责人: Matthew E. Burow
• 金额: $ 28.29万
• 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/8463129
• 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; Prognostic Marker; 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; 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.

摘要 对治疗药物产生抗药性是有效治疗的重大障碍。 癌症的威胁。在分子水平上，这种耐药性的特征是信号和基因的变化。 促进生存和增殖的表达，最终允许进展为更恶性的 表型。这项研究的长期目标是了解MEK5-ERK5信号的作用 乳腺癌发生和耐药的途径及其靶向性研究 治疗干预的策略。使用基因表达谱和细胞信号检测 已经确定并暗示MEK5-ERK5通路是获得性耐药的关键组成部分 协同获得乳腺癌细胞中EMT和ER阴性的表型。我们的初步数据 进一步提示，MEK5信号通过下游转录因子发挥调节作用 EMT调节因子(SLUG、ZEB1、ZEB2)和AKT3的表达。根据这一信息，我们假设 MEK5-ERK5信号通路上调诱导上皮细胞向间充质细胞转化，丢失 ER？的表达，并推动乳腺癌细胞向激素非依赖性和治疗性方向发展 抗性表型。拟议的具体目标旨在为MEK5确立一个角色，定义 在体外和体内发生向耐药表型进展的特定机制。目标1：达到 验证ERK5信号在MEK5介导的乳腺癌发生和发展中所必需的假说 治疗抵抗力。目的#2：验证MEK5-ERK5信号在转移性心脏病发生发展中的作用 内分泌独立和通过破坏ER？信号轴而产生的抵抗。目标3：测试 假设MEK5-ERK5信号轴促进上皮细胞到间充质细胞的转变，ER阴性 和侵袭性表型。在本提案中，我们期望定义并链接MEK5-ERK5信号的直接作用 通路在治疗耐药的形成和促进侵袭性表型的形成中发挥作用 癌细胞。这种联系的建立将把MEK5-ERK5通路定义为潜在的分子 将标志物用作治疗反应的预后指标和预期的分子靶点 用于药理药物开发。