MEK5-Erk5 in breast cancer resistance

MEK5-Erk5 在乳腺癌抵抗中的作用

• 批准号: 7987895
• 负责人: Matthew E. Burow
• 金额: $ 32.24万
• 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/7987895
• 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; Transcriptional Regulation; Up-Regulation; Xenograft procedure; base; cancer cell; design; drug development; effective therapy; epithelial to mesenchymal transition; hormone therapy; in vivo; insight; malignant breast neoplasm; malignant phenotype; molecular marker; mouse model; novel; prognostic indicator; prospective; public health relevance; resistance mechanism; response; slug; small hairpin RNA; therapeutic development; tool; transcription factor; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): 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 ER1-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 ER1 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 ER1-signaling axis. Aim#3: To test the hypothesis that the MEK5-Erk5 signaling axis promotes an epithelial-to-mesenchymal transition, ER1-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. PUBLIC HEALTH RELEVANCE: While endocrine therapies, such as the anti-estrogen tamoxifen and the aromatase inhibitors, are important tools in the treatment of ER(+) breast carcinoma in the adjuvant and metastatic setting some tumors ultimately progresses to hormone-independence and resistance. Here we examine the role and mechanisms of the novel MEK5-Erk5 mitogen-activated protein kinase pathway in the regulation of cell survival and therapeutic resistance of breast cancer cells. We further examine the role of MEK5-Erk5 signaling in the progression of breast cancer cells to an ER1-negative and epithelial-to-mesenchymal transition phenotype. The research in this proposal is about understanding mechanisms of resistance and developing strategies to target and treat breast cancer progression.

描述（由申请人提供）：对治疗剂的抵抗力的发展代表了有效治疗癌症的重要障碍。在分子水平上，这种抗药性的特征是信号传导和基因表达的变化，这些耐药性促进生存和增殖，最终允许发展为更恶性的表型。这项研究的长期目的是了解MEK5-ERK5信号通路在乳腺癌的肿瘤发生和耐药性中的作用，目的是制定针对治疗干预的靶向策略。使用基因表达分析和对细胞信号的检查，我们已将MEK5-ERK5途径鉴定为获得的抗药性坐标的关键组成部分，可在乳腺癌细胞中获得EMT和ER1阴性表型。我们的初步数据进一步表明，MEK5信号通过下游转录因子介导EMT调节剂（SLUG，ZEB1，ZEB2）和AKT3的表达。基于此信息，我们假设MEK5-ERK5信号通路的上调会诱导上皮到间质的转变，ER1表达的丧失，并使乳腺癌细胞不依赖激素依赖性和治疗性抗药性表型。拟议的特定目的旨在为MEK5确定定义特定机制的作用，该机制在体外和体内发生抗性表型。目标＃1：测试MEK5介导的乳腺癌肿瘤发生和治疗性抗性所需的ERK5信号传导的假设。目标＃2：检验以下假设：MEK5-ERK5信号通过破坏ER1信号轴的破坏而发展到内分泌独立和抗性中。目标＃3：测试MEK5-ERK5信号轴促进上皮到间质转变，ER1阴性和侵入性表型的假设。在此提案中，我们希望将MEK5-ERK5信号通路在治疗性耐药性发展中起作用并促进癌细胞中侵袭性表型的直接作用。这种连接的建立将将MEK5-ERK5途径定义为可以用作治疗反应的预后指标，并将其作为药理药物开发的前瞻性分子靶标。 公共卫生相关性：虽然内分泌疗法，例如抗雌激素莫昔芬和芳香酶抑制剂，是辅助和转移性环境中ER（+）乳腺癌治疗某些肿瘤的重要工具，最终发展为激素独立和抗性。在这里，我们研究了新型MEK5-ERK5有丝分裂原激活蛋白激酶途径在细胞存活和乳腺癌细胞治疗性耐药性中的作用和机制。我们进一步研究了MEK5-ERK5信号传导在乳腺癌细胞进展中对ER1阴性和上皮 - 间质转变表型的作用。该提案中的研究是关于理解抗药性机制，并制定靶向和治疗乳腺癌进展的策略。