MEK5-Erk5 in breast cancer resistance

描述（由申请人提供）：对治疗药物的耐药性的发展是有效治疗癌症的重大障碍。在分子水平上，这种耐药性的特征是信号传导和基因表达的变化，从而促进生存和增殖，最终使其发展为更恶性的表型。本研究的长期目标是了解MEK5-Erk5信号通路在乳腺癌肿瘤发生和耐药中的作用，以制定治疗干预的靶向策略。通过基因表达谱和细胞信号的检测，我们发现并暗示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。基于这些信息，我们假设MEK5-Erk5信号通路的上调诱导了上皮细胞向间质细胞的转变，ER1表达的缺失，并驱动乳腺癌细胞向激素不依赖和治疗耐药的表型发展。提出的特异性目标旨在确定MEK5的作用，确定在体外和体内发生抗性表型进展的特定机制。目的1：验证Erk5信号是MEK5介导的乳腺癌肿瘤发生和治疗耐药所必需的假设。目的2：验证MEK5-Erk5信号通过破坏er1信号轴在向内分泌独立性和抗性发展的过程中起作用的假设。目的3：验证MEK5-Erk5信号轴促进上皮细胞向间质细胞转化、er1阴性和侵袭性表型的假设。在本提案中，我们期望定义和链接MEK5-Erk5信号通路在癌症细胞治疗耐药性的发展和促进侵袭性表型中的直接作用。这种联系的建立将定义MEK5-Erk5通路作为潜在的分子标记物，可作为治疗反应的预后指标，并作为药理学药物开发的潜在分子靶点。

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.