MEK5-Erk5 in breast cancer resistance

描述(由申请人提供)：对治疗药物产生抗药性是癌症有效治疗的一个重大障碍。在分子水平上，这种耐药性的特征是信号和基因表达的变化，这些变化促进了生存和增殖，最终允许进展到更恶性的表型。本研究的长期目标是了解MEK5-ERK5信号通路在乳腺癌的发生和耐药中的作用，目的是为治疗干预提供靶向策略。利用基因表达谱和细胞信号检测，我们已经确定并暗示MEK5-ERK5通路是乳腺癌细胞获得EMT和ER1阴性表型的获得性耐药协调的关键组成部分。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向间充质转化，ER1表达缺失，并驱动乳腺癌细胞向激素非依赖性和治疗耐药表型发展。所提出的特定目的是为了确定MEK5的作用，确定在体外和体内发生耐药表型的具体机制。目的#1：验证ERK5信号在MEK5介导的乳腺癌发生和治疗耐药中所必需的假设。目的#2：验证MEK5-ERK5信号通过破坏ER1信号轴在内分泌非依赖性和耐药过程中发挥作用的假设。目的#3：验证MEK5-ERK5信号轴促进上皮向间充质转化、ER1阴性和侵袭性表型的假设。在这项提案中，我们希望定义和联系MEK5-ERK5信号通路在肿瘤细胞治疗耐药的发展和促进侵袭性表型的发展中所起的直接作用。这种联系的建立将把MEK5-ERK5通路定义为潜在的分子标志物，可用作治疗反应的预后指标，并作为药理药物开发的预期分子靶点。 公共卫生相关性：虽然内分泌疗法，如抗雌激素的他莫昔芬和芳香酶抑制剂，是在辅助和转移环境下治疗ER()乳腺癌的重要工具，但一些肿瘤最终会进展到激素非依赖性和耐药性。在这里，我们研究了新的MEK5-ERK5丝裂原活化蛋白激酶通路在调节乳腺癌细胞存活和治疗耐药中的作用和机制。我们进一步研究了MEK5-ERK5信号在乳腺癌细胞向ER1阴性和上皮向间充质转化表型发展中的作用。这项提案中的研究是关于了解耐药性的机制，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.