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Mechanisms of FoxA1 Latent Enhancer Formation in Response to Proinflammatory Signaling in Hormone Dependent Cancers

FoxA1 潜在增强子形成响应激素依赖性癌症促炎信号的机制

基本信息

批准号：
9405057
负责人：
Hector Luis Franco
金额：
$ 24.9万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-17 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9405057
关键词：
Address Advisory Committees Affect Androgen Receptor Animal Model Aptitude Attention Award Binding Binding Sites Biochemistry Biological Biological Assay Biological Models Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer Risk Factor Cancer Biology Cells ChIP-seq Chromatin Code Communities DNA-Binding Proteins Data Development Developmental Process Endocrine system Enhancers Environment Estrogen Receptor alpha Estrogen Receptors Estrogens Event Faculty Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genome Genomics Goals Growth Hormones Immune system Inflammation Inflammatory Institutes Knock-in Mouse Knock-out Knockout Mice Knowledge Laboratories Leadership Learning Ligands Link Location Malignant Neoplasms Mammary gland Mediating Medical Medical center Mentors Messenger RNA Methodology Molecular Molecular Biology Motivation Mus Mutation Neoplasm Metastasis Nuclear Receptors Nucleic Acid Regulatory Sequences Outcome Phase Phenotype Physiological Processes Play Polymerase Positioning Attribute Post-Translational Protein Processing Prevention Principal Investigator Proteins Proteomics Publications Research Research Proposals Research Technics Resistance Resistance development Role Science Signal Pathway Signal Transduction Signaling Molecule Site TNF gene Technology Testing Time Training Translating United States National Academy of Sciences Universities Untranslated RNA Work Xenograft procedure base cancer cell cancer therapy career cytokine design experience experimental study faculty research hormone therapy knock-down malignant breast neoplasm member mouse model next generation sequencing novel predict clinical outcome promoter public health relevance receptor function response skills tenure track transcription factor treatment response tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Inflammation is known to have a paradoxical effect on cancers being able to both promote and inhibit the growth of tumors. It is known that crosstalk between the endocrine and immune systems play key roles in determining the phenotypes and outcomes of hormone dependent cancers such as breast cancer. The studies outlined in this proposal are poised to determine how the estrogen and proinflammatory signaling pathways converge in cancer cells to regulate the expression of many genes important for initiation, growth and metastasis. The responses of cancer cells to estrogens and proinflammatory signaling molecules are largely mediated by DNA binding proteins, known as transcription factors, that bind to regulatory regions of the genome to change the expression of many target genes. More specifically, this study will focus the inflammatory-mediated mechanisms that influence the function of the pioneer transcription factor FoxA1. The preliminary data for this research proposal shows that proinflammatory signaling, in cooperation with estrogen signaling, causes FoxA1 to bind to regions of the genome that were thought to be dormant or latent in breast cancer cells. This, in turn, activates the expression of a novel set of genes that are stron predictors of clinical outcomes in breast cancer patients. This work is significant because it provides a framework for the integration of two of the major signaling cascades that exacerbate tumorigenesis. The applicant will use state-of-the-art molecular biology, genomic and proteomic methodologies in both cell-based and mouse models of breast cancer, to address the aims of this study. This integrated approach will allow for systematic analysis of FoxA1 function, and the downstream consequences, during proinflammatory signaling in breast cancer. The goal of the applicant is to use the academic, research and leadership training received during the tenure of this award to successfully transition into an independent tenure track faculty position. As the principal investigator of a competitive research group at a major university or medical center, the motivation for the science being done in the applicant's laboratory will be to discover new avenues for the prevention and treatment of cancer by understanding how gene regulation and cell signaling influence cancer biology. To date, the applicant's research demonstrates an aptitude for molecular biology, biochemistry and next-generation sequencing technologies and the goal for the mentored phase of training is to gain experience with the use of proteomics and animal models. UT Southwestern Medical Center is an idea location for completion of the mentored phase because it is a research-oriented university that provides an exceptional and highly interactive scientific and intellectual environment. UT Southwestern's research faculty include 18 members of the National Academy of Sciences, 13 members of the Howard Hughes Medical Institute, and five Nobel Laureates. Frequent interactions with the candidate's primary mentor and advisory committee will continue to develop the research techniques, scientific knowledge and leadership skills needed to transition into an independent career.

描述（由申请人提供）：已知炎症对癌症具有矛盾的作用，能够促进和抑制肿瘤的生长。众所周知，内分泌系统和免疫系统之间的串扰在确定乳腺癌等激素依赖性癌症的表型和结果方面发挥着关键作用。该提案中概述的研究旨在确定雌激素和促炎信号通路如何在癌细胞中汇聚，以调节许多对起始、生长和转移至关重要的基因的表达。癌细胞对雌激素和促炎信号分子的反应很大程度上是由 DNA 结合蛋白（称为转录因子）介导的，这些蛋白与基因组的调节区域结合以改变许多靶基因的表达。更具体地说，本研究将重点关注影响先锋转录因子 FoxA1 功能的炎症介导机制。这项研究计划的初步数据表明，促炎症信号传导与雌激素信号传导相结合，导致 FoxA1 与乳腺癌细胞中被认为处于休眠或潜伏状态的基因组区域结合。这反过来又激活了一组新基因的表达，这些基因是乳腺癌患者临床结果的有力预测因子。这项工作意义重大，因为它为整合加剧肿瘤发生的两个主要信号级联反应提供了框架。申请人将在乳腺癌细胞模型和小鼠模型中使用最先进的分子生物学、基因组和蛋白质组学方法来实现本研究的目标。这种综合方法将允许系统分析乳腺癌促炎症信号传导过程中的 FoxA1 功能及其下游后果。申请人的目标是利用在该奖项任职期间接受的学术、研究和领导力培训，成功过渡到独立的终身教授职位。作为主要大学或医疗中心的竞争性研究小组的首席研究员，申请人实验室正在进行的科学研究的动机将是通过了解基因调控和细胞信号传导如何影响癌症生物学来发现预防和治疗癌症的新途径。迄今为止，申请人的研究表明了其在分子生物学、生物化学和下一代测序技术方面的能力，培训指导阶段的目标是获得使用蛋白质组学和动物模型的经验。德克萨斯大学西南医学中心是完成指导阶段的理想地点，因为它是一所研究型大学，提供卓越且高度互动的科学和智力环境。 UT Southwestern 的研究人员包括 18 名美国国家科学院院士、13 名霍华德休斯医学研究所成员和 5 名诺贝尔奖获得者。与候选人的主要导师和咨询委员会的频繁互动将继续发展过渡到独立职业所需的研究技术、科学知识和领导技能。