Characterization of a Novel lncRNA in Breast Cancer

项目摘要 乳腺癌是女性中最常见的癌症，包括一组不同的疾病， 乳腺癌的早期症状是什么？ER/PR/Her 2三阴性乳腺癌 （TNBC）亚型是最具侵袭性的肿瘤类型，并且具有较差的预后。因此，必须确定 并表征用于治疗TNBC的新的治疗靶点。尽管数百种基因突变 已知在促进癌症中，长链非编码RNA（lncRNA）正在成为肿瘤的关键组分。 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体，许多种类的蛋白质（包括转录调节因子）， 和其他RNA分子，以调节基因组结构和基因表达。或偏差已查明 作为与不同乳腺癌亚型和等级相关的诊断和/或预后因素。然而 相对较少的是功能和机械特征，这是发展的要求。 未来的干预策略，以防止TNBC进展。初步数据显示， 与不同的癌细胞亚型有关。这一建议的重点是理解一部小说的机制 在TNBC细胞中选择性表达的lncRNA，MANCR。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。该提案针对 假设MANCR表达支持TNBC细胞的基因组稳定性， 可以通过直接表征lncRNA相互作用组来鉴定对该效应有贡献的基因。为了验证这一 假设，三个具体的目标将解决机制和临床前研究这种lncRNA。 具体目的1：确定通过RUNX 2和AP-1调节因子对TNBC中MANCR表达的调节 元素具体目的2：建立MANCR在TNBC细胞中的作用的机制，其诱导调节性细胞凋亡。 参与维持TNBC基因组稳定性的因素。具体目标3：证明这种lncRNA影响 体内肿瘤生长。 影响：这些研究将首次确定一种新的lncRNA相关的调控机制。 关于TNBC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不存在于 几乎每个正常组织，因此限制了作为治疗剂的脱靶效应。我们预计， 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 来治疗TNBC患者

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.