Characterization of a Novel lncRNA in Breast Cancer

乳腺癌中新型 lncRNA 的表征

基本信息

批准号：
10055784
负责人：
Kirsten Tracy
金额：
$ 7.51万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10055784
关键词：
Address Affect Binding Biological Markers Breast Cancer Cell Breast Cancer cell line Breast Epithelial Cells CRISPR interference CRISPR/Cas technology Cell Cycle Cell Death Cell Proliferation Cell physiology Cells ChIP-seq Chromatin Chromatin Structure Clustered Regularly Interspaced Short Palindromic Repeats DNA DNA Damage DNA Sequence Alteration Data Defect Dependence Diagnostic or Prognostic Factor Disease Epigenetic Process Estrogen receptor positive Fatty acid glycerol esters Fellowship Future Gene Expression Gene Expression Profiling Genetic Enhancer Element Genetic Transcription Genome Genome Stability Genomic Instability Growth Homeostasis Intervention Investigation Ionizing radiation Knowledge MCF10A cells MCF7 cell MDA MB 231 MDA-MB-468 Malignant Neoplasms Mediating Metastatic breast cancer Modeling Molecular NOD/SCID mouse Neoplasm Metastasis Normal Cell Normal tissue morphology Outcome Outcome Study Patients Phenotype Primary Neoplasm Prognosis Property Proteins Publishing RNA RNA I Regulation Regulatory Element Role Small RNA Structure Testing Therapeutic Agents Therapeutic Intervention Time Tissues Training Transcription Factor AP-1 Untranslated RNA Woman advanced breast cancer aggressive breast cancer bone breast cancer progression cancer cell cancer cell subtype cancer subtypes chromatin immunoprecipitation clinical application clinically relevant clinically translatable differential expression epigenetic regulation genome editing genome integrity in vivo knock-down malignant breast neoplasm mammary neoplastic cell new therapeutic target novel overexpression pre-clinical prevent promoter selective expression targeted treatment therapeutic target therapy design transcriptome transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor growth tumor xenograft

项目摘要

PROJECT SUMMARY Breast cancer is the most prevalent cancer among women and encompasses a group of different diseases as a result of the many different subtypes of breast cancer cells. The ER/PR/Her2 triple negative breast cancer (TNBC) subtype is the most aggressive tumor type and has a poor prognosis. Thus it is imperative to identify and characterize novel therapeutic targets for the treatment of TNBC. While hundreds of genetic mutations are known in promoting cancer, long non-coding RNAs (lncRNAs) are emerging as critical components of the epigenetic regulation of normal cellular functions and have been associated with several cancers. LncRNAs function by forming interactomes with chromatin, many classes of proteins (including transcriptional regulators), and other RNA molecules, to regulate both genome structure and gene expression. They have been identified as diagnostic and/or prognostic factors associated with different breast cancer subtypes and grades. However relatively few have been functionally and mechanistically characterized, which is a requirement for developing future intervention strategies to prevent TNBC progression. Preliminary data has identified specific lncRNAs associated with distinct cancer cell subtypes. This proposal focuses on understanding the mechanism of a novel lncRNA, MANCR that is selectively expressed in TNBC cells. Our published findings have shown that MANCR inhibition results in increased genomic instability and tumor cell death in TNBC. This proposal addresses the hypothesis that MANCR expression supports genomic stability of TNBC cells and that the mechanisms contributing to this effect can be identified through direct characterization of the lncRNA interactome. To test this hypothesis, three specific aims will address both mechanistic and preclinical investigations into this lncRNA. Specific Aim 1: Determine the regulation of MANCR expression in TNBC by RUNX2 and AP-1 regulatory elements. Specific Aim 2: Establish mechanisms for the role of MANCR in TNBC cells that induce regulatory factors involved in maintaining genomic stability of TNBC. Specific Aim 3: Demonstrate that this lncRNA affects tumor growth in vivo. Impact: These studies will, for the first time, identify the regulatory mechanisms of a novel lncRNA associated with TNBC. Our findings will greatly impact on its potential as a therapeutic target because MANCR is absent in nearly every normal tissue, thus limiting off-target effects as a therapeutic agent. We anticipate that knowledge of the molecular and pre-clinical findings of MANCR will be the basis for future studies in the design of therapies to treat patients with TNBC.

项目概要乳腺癌是女性中最常见的癌症，包含一组不同的疾病乳腺癌细胞许多不同亚型的结果。 ER/PR/Her2 三阴性乳腺癌 (TNBC) 亚型是最具侵袭性的肿瘤类型，预后较差。因此必须要识别并确定治疗 TNBC 的新治疗靶点。虽然有数百种基因突变众所周知，长链非编码 RNA (lncRNA) 正在成为癌症的关键组成部分。正常细胞功能的表观遗传调控，并与多种癌症有关。长链非编码RNA 通过与染色质、许多类别的蛋白质（包括转录调节因子）形成相互作用组来发挥作用，和其他RNA分子，调节基因组结构和基因表达。他们已被识别作为与不同乳腺癌亚型和级别相关的诊断和/或预后因素。然而相对较少的功能和机械特征，这是开发的要求预防 TNBC 进展的未来干预策略。初步数据已确定特定的lncRNA 与不同的癌细胞亚型相关。该提案的重点是理解小说的机制 lncRNA，MANCR，在TNBC细胞中选择性表达。我们发表的研究结果表明 MANCR 抑制导致 TNBC 中基因组不稳定性增加和肿瘤细胞死亡。该提案解决了假设 MANCR 表达支持 TNBC 细胞的基因组稳定性，其机制可以通过 lncRNA 相互作用组的直接表征来识别导致这种效应的因素。为了测试这个根据假设，三个具体目标将解决对该 lncRNA 的机械和临床前研究。具体目标1：确定RUNX2和AP-1调节对TNBC中MANCR表达的调节元素。具体目标 2：建立 MANCR 在 TNBC 细胞中的作用机制，诱导调节维持 TNBC 基因组稳定性的因素。具体目标 3：证明该 lncRNA 影响体内肿瘤生长。影响：这些研究将首次确定一种新型 lncRNA 相关的调控机制。与 TNBC 合作。我们的研究结果将极大地影响其作为治疗靶点的潜力，因为 MANCR 在几乎所有正常组织，从而限制了作为治疗剂的脱靶效应。我们预计这些知识 MANCR 的分子和临床前研究结果将成为未来治疗设计研究的基础治疗 TNBC 患者。