The role of mixed lineage leukemia (MLL/KMT2) core complex in directing FOXQ1 activity for triple negative breast cancer progression

混合谱系白血病 (MLL/KMT2) 核心复合物在指导 FOXQ1 活性对三阴性乳腺癌进展中的作用

• 批准号: 9901354
• 负责人: Allison Mitchell
• 金额: $ 4.28万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901354
• 关键词: ASH2L gene; Address; Affinity Chromatography; Amino Acids; Attenuated; Automobile Driving; Binding; Biochemical; Biological; Biological Models; Breast Cancer Patient; Breast Epithelial Cells; Cell Line; Cell Survival; Cells; ChIP-seq; Chromatin; Clinical; Co-Immunoprecipitations; Complex; Coupled; DNA; Data; Deletion Mutation; Dependence; Development; Disease Progression; Distant; Distant Metastasis; Doxorubicin; Epigenetic Process; Expression Profiling; FOXC2 gene; FOXQ1 gene; Family; Fostering; Foundations; Gene Activation; Gene Expression; Gene Targeting; Generations; Genes; Genetic Transcription; High-Throughput DNA Sequencing; Histones; Human; Immunocompromised Host; In Vitro; Invaded; Investigation; Lysine; Malignant Epithelial Cell; Maps; Mass Spectrum Analysis; Mediating; Metastatic Neoplasm to the Lung; Mixed-Lineage Leukemia; Modeling; Molecular; Mutate; Mutation; NU/NU Mouse; Nature; Neoplasm Metastasis; Oncogenes; Oncogenic; Outcome; Paclitaxel; Pharmacology; Pharmacotherapy; Phenotype; Point Mutation; Population; Prevalence; Process; Promoter Regions; Protein Truncation; Proteins; Publishing; Recombinants; Recurrence; Regulation; Regulator Genes; Regulatory Element; Resistance; Role; SET Domain; Signal Pathway; Signal Transduction; Solid Neoplasm; Structural Models; Structure; Subfamily lentivirinae; TWIST1 gene; Transcription Coactivator; Transitional Cell; Xenograft procedure; breast cancer progression; cancer cell; cancer subtypes; chemotherapy; chromatin immunoprecipitation; epithelial to mesenchymal transition; experimental study; histone methyltransferase; improved; improved mobility; in silico; in vivo; insight; knock-down; malignant breast neoplasm; mammary epithelium; member; mutant; overexpression; prevent; programs; protein complex; recruit; screening; standard of care; stem; stemness; targeted treatment; trait; transcription factor; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor progression

Project Summary Triple negative breast cancer (TNBC) accounts for up to 20% of all breast cancer cases and presents with the worst clinical outcomes due to lack of targeted therapeutic options and rapid onset of tumor recurrence, chemotherapy resistance and metastasis. A phenotypic change within the cancer cells, known as the epithelial to mesenchymal transition (EMT), has been observed to promote cell survival against drug treatment and foster metastatic progression. FOXQ1 has been identified as a potent oncogenic transcription factor that induces the EMT phenotype in TNBC. Preliminary data have uncovered a potential mechanism for the regulation of FOXQ1 transcriptional activity. Protein interaction screening identified binding between FOXQ1 and the MLL core complex, a prominent epigenetic regulatory complex. Further investigation identified that FOXQ1 and the MLL core complex co-localize within the chromatin regions of transcriptional regulatory elements of genes with known functions in inducing EMT. This suggests that the MLL core complex is functioning as a transcriptional coactivator for FOXQ1 to drive the EMT transcription program and resultant tumor progression. Aim 1 will fully interrogate the biochemical nature of this protein interaction by mapping the structure of the FOXQ1-MLL core complex binding pocket. Identification of the critical interacting domains will be accomplished by GST-pull down with recombinant purified proteins. Mapping will be accomplished by successive generation of protein truncations and point mutations, as well as, in silico structural modeling. Aim 2 will elaborate on the functional implication of the FOXQ1-MLL complex interaction. The biochemical insights gained from Aim 1 will but utilized to generate a FOXQ1 construct with induced synthetic mutations that diminish the ability of FOXQ1 to interact and recruit the MLL core complex. The resultant FOXQ1 mutant will be ectopically expressed in a cell line model of breast EMT. The model system will be used to assess the extent to which disrupting FOXQ1 binding to the MLL core complex attenuates the ability to drive features of EMT, cell invasion and distant metastatic progression in vivo. The results of this study will be used to evaluate the efficacy of targeting the FOXQ1-MLL core complex protein interaction as a potential pharmacologic strategy to prevent tumor progression in triple negative breast cancer.

项目总结