Characterization of a Novel lncRNA in Breast Cancer

乳腺癌中新型 lncRNA 的表征

• 批准号: 9918758
• 负责人: Kirsten Tracy
• 金额: $ 6.93万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918758
• 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; Mammary gland; Mediating; Metastatic breast cancer; Modeling; Molecular; NOD/SCID mouse; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Outcome; Outcome Study; Patients; Phenotype; Primary Neoplasm; 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; 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; neoplastic cell; new therapeutic target; novel; outcome forecast; 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

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.

项目摘要 乳腺癌是女性中最普遍的癌症，包括一组不同的疾病 乳腺癌细胞的许多不同亚型的结果。 ER/PR/HER2三重阴性乳腺癌 （TNBC）亚型是最具侵略性的肿瘤类型，预后较差。因此，必须识别 并表征了用于治疗TNBC的新型治疗靶标。而数百个遗传突变是 在促进癌症中已知，长期非编码RNA（LNCRNA）已成为临界成分 正常细胞功能的表观遗传调节，并与几种癌症有关。 lncrnas 通过与染色质形成相互作用的功能，许多类别的蛋白质（包括转录调节剂）， 和其他RNA分子，以调节基因组结构和基因表达。他们已经确定 作为与不同的乳腺癌亚型和成绩相关的诊断和/或预后因素。然而 相对较少的功能和机理表征，这是开发的要求 预防TNBC进展的未来干预策略。初步数据已经确定了特定的lncrnas 与不同的癌细胞亚型相关。该提议重点是理解小说的机制 lncRNA，在TNBC细胞中选择性表达的mancr。我们已发表的发现表明Mancr 抑制作用导致TNBC中的基因组不稳定性和肿瘤细胞死亡增加。该提议解决了 MANCR表达支持TNBC细胞的基因组稳定性和机制的假设 可以通过直接表征lncRNA Itspetnolome组来确定对这种效果的贡献。测试这个 假设，三个具体目标将解决该LNCRNA的机械和临床前研究。 特定目标1：通过RUNX2和AP-1调节确定TNBC中MANCR表达的调节 元素。具体目标2：建立MANCR在TNBC细胞中的作用的机制 维持TNBC基因组稳定性的因素。特定目的3：证明此lncRNA影响 体内肿瘤生长。 影响：这些研究将首次确定新型lncRNA相关的调节机制 与TNBC。我们的发现将极大地影响其作为治疗目标的潜力，因为MANCR不存在 几乎每个正常组织，因此限制了作为治疗剂的脱靶效应。我们期待这一知识 MANCR的分子和临床前发现将成为未来研究的基础。 治疗TNBC患者。