Mechanisms of MMP-Induced Malignancy in Breast Cells

MMP 诱发乳腺细胞恶性肿瘤的机制

• 批准号: 7265038
• 负责人: Derek C Radisky
• 金额: $ 28.69万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7265038
• 关键词: Affect; Alternative Splicing; Aneuploidy; Breast; Cell Cycle; Cell surface; Cells; Centrosome; Characteristics; Chromosome abnormality; Chromosomes; Cleaved cell; Clinical Trials; Cultured Cells; Data; Development; E-Cadherin; Elements; Endopeptidases; Epithelial; Epithelial Cells; Event; Exposure to; Extracellular Matrix; Failure; Gene Expression; Generations; Genes; Genetic Transcription; Genome Stability; Genomic Instability; Genomics; Growth; Growth Factor; Growth and Development function; Hydrolysis; Invasive; Investigation; Knowledge; Malignant - descriptor; Malignant Neoplasms; Mammary gland; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Mesenchymal; Mitotic; Modeling; Morphogenesis; Mus; Names; Neoplasm Metastasis; Pathologic Processes; Peptide Hydrolases; Phosphotransferases; Physiological Processes; Production; Protein Binding; Protein Isoforms; Proteolysis; Proteomics; Publishing; RNA Interference; Reactive Oxygen Species; Regulator Genes; Relative (related person); Reporter; Research Design; Research Personnel; Role; Series; Snails; Staging; Stromelysin 1; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Organisms; Tumor Angiogenesis; Tumor Suppressor Proteins; Wound Healing; anti-cancer therapeutic; base; human STK6 protein; improved; malignant breast neoplasm; mouse model; novel; programs; promoter; research study; transcription factor; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Matrix metalloproteinases (MMPs) are essential for many physiological processes, but inappropriate expression of MMPs can facilitate the development and progression of tumors. Recognition of the relationship between MMPs and malignancy led to clinical trials of broad-spectrum MMP inhibitors as cancer therapeutics, but the results were disappointing. The failure of the clinical trials was due in large part to the propensity of the MMP inhibitors to inhibit essential physiological processes. Therapeutic strategies that target tumor-specific MMP-dependent effects may prove more promising. Previous studies and our preliminary data show that exposure of mammary epithelial cells to selected MMPs causes cleavage of a cell surface molecule that stimulates cellular production of reactive oxygen species (ROS). MMP-dependent production of ROS causes cells to undergo epithelial-mesenchymal transition (EMT), a fundamental phenotypic alteration associated with progression to metastasis, and compromises the cellular genomic stability. Our long-term objective is to identify the specific steps associated with the MMP-induced malignant transformation so as to determine potential points for therapeutic intervention. To do this, we propose (1) to identify the proteolytic target of MMPs that stimulates the development of ROS, (2) to determine roles of transcription factors Snail and Twist in MMP/ROS-induction of EMT, and (3) to define how MMP/ROS stimulate genomic instability. In Aim 1, investigations of the specific role of cleavage of E-cadherin by MMPs will be supplemented by a proteolytic screen for additional/alternative targets. In Aim 2, we will identify the MMP-induced factors responsible for the increased expression of Snail and Twist, and will dissect the relative role of these transcription factors on the MMP-induced EMT. In Aim 3, we will examine how MMP/ROS induce cellular aneuploidy and mitotic abnormalities through stimulation of centrosome amplification. We expect that by elucidating the chain of events in the induction of EMT and genomic instability by MMPs, we will be able to identify novel promising points for therapeutic intervention in breast cancer.

描述（申请人提供）：基质金属蛋白酶（MMP）对于许多生理过程至关重要，但MMP的不当表达会促进肿瘤的发生和进展。 对 MMP 与恶性肿瘤之间关系的认识导致了广谱 MMP 抑制剂作为癌症治疗药物的临床试验，但结果令人失望。 临床试验的失败很大程度上是由于 MMP 抑制剂抑制基本生理过程的倾向。 针对肿瘤特异性 MMP 依赖性效应的治疗策略可能被证明更有希望。 先前的研究和我们的初步数据表明，乳腺上皮细胞暴露于选定的 MMP 会导致细胞表面分子裂解，从而刺激细胞产生活性氧 (ROS)。 MMP 依赖性 ROS 产生导致细胞经历上皮间质转化 (EMT)，这是一种与转移进展相关的基本表型改变，并损害细胞基因组稳定性。 我们的长期目标是确定与 MMP 诱导的恶性转化相关的具体步骤，以确定潜在的治疗干预点。 为此，我们建议 (1) 确定刺激 ROS 发展的 MMP 蛋白水解靶点，(2) 确定转录因子 Snail 和 Twist 在 MMP/ROS 诱导 EMT 中的作用，以及 (3) 定义MMP/ROS 如何刺激基因组不稳定。 在目标 1 中，对 MMP 裂解 E-钙粘蛋白的具体作用的研究将通过针对其他/替代靶标的蛋白水解筛选来补充。 在目标 2 中，我们将鉴定导致 Snail 和 Twist 表达增加的 MMP 诱导因子，并剖析这些转录因子在 MMP 诱导的 EMT 中的相对作用。 在目标 3 中，我们将研究 MMP/ROS 如何通过刺激中心体扩增来诱导细胞非整倍性和有丝分裂异常。 我们期望通过阐明 MMP 诱导 EMT 和基因组不稳定性的一系列事件，我们将能够确定乳腺癌治疗干预的新希望点。