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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cut homeobox 1 causes chromosomal instability by promoting bipolar division after cytokinesis failure
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Cut homeobox 1 causes chromosomal instability by promoting bipolar division after cytokinesis failure

机译:切下的同源盒1通过促进胞质分裂失败后促进双极分裂而导致染色体不稳定

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摘要

Cell populations able to generate a large repertoire of genetic variants have increased potential to generate tumor cells that survive through the multiple selection steps involved in tumor progression. A mechanism for the generation of aneuploid cancer cells involves passage through a tetraploid stage. Supernumerary cen-trosomes, however, can lead to multipolar mitosis and cell death. Using tissue culture and transgenic mouse models of breast cancer, we report that Cut homeobox 1 (CUX1) causes chromosomal instability by activating a transcriptional program that prevents multipolar divisions and enables the survival of tetraploid cells that evolve to become genetically unstable and tumorigenic. Transcriptional targets of CUX1 involved in DNA replication and bipolar mitosis defined a gene expression signature that, across 12 breast cancer gene expression datasets, was associated with poor clinical outcome. The signature not only was higher in breast tumor subtypes of worse prognosis, like the basal-like and HER2~+ subtypes, but also identified poor outcome among estrogen receptor-positiveode-negative tumors, a subgroup considered to be at lower risk. The CUX1 signature therefore represents a unique criterion to stratify patients and provides insight into the molecular determinants of poor clinical outcome.
机译:能够产生大量遗传变异的细胞群体具有更高的潜力,可以产生通过参与肿瘤进展的多个选择步骤而存活的肿瘤细胞。产生非整倍性癌细胞的机制涉及通过四倍体阶段。然而,多余的中心体会导致多极有丝分裂和细胞死亡。使用组织培养和乳腺癌的转基因小鼠模型,我们报道,Cut homeobox 1(CUX1)通过激活防止多极分裂的转录程序并导致四倍体细胞存活,从而发展成遗传上不稳定的和致瘤的,从而导致染色体不稳定。参与DNA复制和双极有丝分裂的CUX1转录目标定义了一个基因表达特征,该特征在12个乳腺癌基因表达数据集中与不良的临床结果相关。签名不仅在预后较差的乳腺肿瘤亚型中较高,如基底样和HER2〜+亚型,而且在雌激素受体阳性/淋巴结阴性肿瘤中被确认为不良结果,该亚组被认为风险较低。因此,CUX1签名代表了对患者进行分层的独特标准,并提供了对不良临床结果的分子决定因素的深入了解。

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  • 作者单位

    Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC,Canada H3A 1A3,Departments of Biochemistry, McGill University, Montreal, QC,Canada H3A 1A3;

    Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC,Canada H3A 1A3,Departments of Biochemistry, McGill University, Montreal, QC,Canada H3A 1A3;

    Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC,Canada H3A 1A3,McGill Centre for Bioinformatics, McGill University, Quebec, QC, Canada H3G 0B1;

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;

    Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC,Canada H3A 1A3,Departments of Biochemistry, McGill University, Montreal, QC,Canada H3A 1A3;

    Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC,Canada H3A 1A3,Departments of Biochemistry, McGill University, Montreal, QC,Canada H3A 1A3;

    Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC,Canada H3A 1A3;

    Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC,Canada H3A 1A3,McGill Centre for Bioinformatics, McGill University, Quebec, QC, Canada H3G 0B1;

    Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC,Canada H3A 1A3,Departments of Biochemistry, McGill University, Montreal, QC,Canada H3A 1A3,Departments of Oncology, McGill University, Montreal, QC,Canada H3A 1A3,Departments of Medicine, McGill University, Montreal, QC,Canada H3A 1A3;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    tetraploidy; transcription factor; spindle assembly checkpoint;

    机译:四倍体;转录因子;主轴装配检查点;

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