MEK5-Erk5 in breast cancer resistance

描述（由申请人提供）：对治疗剂产生耐药性是有效治疗癌症的一个重大障碍。在分子水平上，这种耐药性的特征在于信号传导和基因表达的变化，这些变化促进了存活和增殖，最终允许进展为更恶性的表型。本研究的长期目标是了解MEK 5-Erk 5信号通路在乳腺癌的肿瘤发生和耐药性中的作用，目的是开发治疗干预的靶向策略。使用基因表达谱分析和细胞信号转导的检查，我们已经确定并暗示MEK 5-Erk 5途径作为获得性耐药的关键组成部分，其与乳腺癌细胞中EMT和ER 1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调节因子（SLUG，ZEB 1，ZEB 2）和AKT 3的表达。基于这些信息，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的转化，ER 1表达的丧失，并驱动乳腺癌细胞进展为非依赖性和治疗抗性表型。拟定的特定目的旨在确定MEK 5的作用，定义体外和体内发生耐药表型进展的特定机制。目的#1：检验ERK 5信号传导是MEK 5介导的乳腺癌肿瘤发生和治疗抗性所需的假设。目标二：为了验证MEK 5-Erk 5信号传导通过破坏ER 1信号传导轴在内分泌不依赖性和抵抗性进展中发挥作用的假设。目的#3：检验MEK 5-Erk 5信号传导轴促进上皮-间充质转化、ER 1阴性和侵袭性表型的假设。在该提案中，我们期望定义和链接MEK 5-Erk 5信号通路在治疗抗性的发展中发挥的直接作用，并促进癌细胞中的侵袭性表型。这种联系的建立将MEK 5-Erk 5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药理学药物开发的前瞻性分子靶点。 公共卫生相关性：虽然内分泌疗法，如抗雌激素他莫昔芬和芳香化酶抑制剂，是在辅助和转移背景下治疗ER（+）乳腺癌的重要工具，但一些肿瘤最终进展为非依赖性和耐药性。在这里，我们研究的作用和机制，新的MEK 5-Erk 5丝裂原活化蛋白激酶途径在乳腺癌细胞的细胞存活和耐药性的调节。我们进一步研究了MEK 5-Erk 5信号在乳腺癌细胞向ER 1阴性和上皮向间充质转化表型进展中的作用。该提案中的研究是关于了解耐药机制，并制定针对和治疗乳腺癌进展的策略。

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.