Characterization of a Novel lncRNA in Breast Cancer

项目总结 乳腺癌是女性中最常见的癌症，包括一组不同的疾病 这是许多不同亚型的乳腺癌细胞的结果。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，必须确定 并表征了治疗TNBC的新治疗靶点。虽然数以百计的基因突变是 众所周知，在促进癌症，长的非编码RNA(LncRNAs)正在成为 表观遗传对正常细胞功能的调节，并与几种癌症有关。IncRNAs 通过与染色质、多种蛋白质(包括转录调节因子)形成相互作用而发挥作用， 和其他RNA分子，来调节基因组结构和基因表达。他们的身份已经被确认 作为与不同乳腺癌亚型和分级相关的诊断和/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lncRNA 与不同的癌细胞亚型有关。这一建议侧重于理解一部小说的机制 LncRNA，在TNBC细胞中选择性表达的MANCR。我们发表的研究结果表明，MANCR 抑制会导致TNBC中基因组的不稳定性增加和肿瘤细胞死亡。这项建议解决了 假设MANCR的表达支持TNBC细胞的基因组稳定性及其机制 对这一效应的贡献可以通过直接表征lncRNA相互作用体来确定。为了测试这一点 假设，三个具体的目标将解决对这种lncRNA的机械性和临床前研究。 特异性目标1：确定RUNX2和AP-1对TNBC中MANCR表达的调节 元素。具体目标2：建立MANCR在TNBC细胞中诱导调控的机制 影响TNBC基因组稳定性的因素。具体目标3：证明这种lncRNA影响 肿瘤在体内生长。 影响：这些研究将首次确定一种新的与lncRNA相关的调控机制。 与TNBC合作。我们的发现将极大地影响其作为治疗靶点的潜力，因为MANCR在 几乎所有的正常组织，因此限制了作为治疗剂的非靶点效应。我们期待着这一知识 MANCR的分子和临床前发现将是未来治疗设计研究的基础 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.