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首页> 外文期刊>Nature >Targeting TRIM37-dri ven centrosome dysfunction in 17q23-amplified breast cancer
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Targeting TRIM37-dri ven centrosome dysfunction in 17q23-amplified breast cancer

机译：靶向Trim37-DRI VEN Centrosome功能障碍于17Q23-扩增的乳腺癌

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摘要

TRIM37overexpression promotes centrosome dysfunction that drives genomic instability in breast cancer cell lines containing the recurrent 17q23 amplicon, revealing a vulnerability that can be targeted to eliminate cancer cells.Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer(1,2). The success of poly-ADP ribose polymerase inhibitors in the treatment of breast cancers that are deficient in homologous recombination exemplifies the utility of synthetically lethal genetic interactions in the treatment of breast cancers that are driven by genomic instability(3). Given that defects in homologous recombination are present in only a subset of breast cancers, there is a need to identify additional driver mechanisms for genomic instability and targeted strategies to exploit these defects in the treatment of cancer. Here we show that centrosome depletion induces synthetic lethality in cancer cells that contain the 17q23 amplicon, a recurrent copy number aberration that defines about 9% of all primary breast cancer tumours and is associated with high levels of genomic instability(4-6). Specifically, inhibition of polo-like kinase 4 (PLK4) using small molecules leads to centrosome depletion, which triggers mitotic catastrophe in cells that exhibit amplicon-directed overexpression ofTRIM37. To explain this effect, we identify TRIM37 as a negative regulator of centrosomal pericentriolar material. In 17q23-amplified cells that lack centrosomes, increased levels of TRIM37 block the formation of foci that comprise pericentriolar material-these foci are structures with a microtubule-nucleating capacity that are required for successful cell division in the absence of centrosomes. Finally, we find that the overexpression of TRIM37 causes genomic instability by delaying centrosome maturation and separation at mitotic entry, and thereby increases the frequency of mitotic errors. Collectively, these findings highlightTRIM37-dependent genomic instability as a putative driver event in 17q23-amplified breast cancer and provide a rationale for the use of centrosome-targeting therapeutic agents in treating these cancers.
机译：Trim37过表达促进了含有复发性17Q23扩增子的乳腺癌细胞系中的基于乳腺癌细胞系中的内分泌功能障碍，揭示了可以靶向消除癌细胞的脆弱性。概念不稳定是癌症的标志，在启动和发展中具有核心作用乳腺癌（1,2）。聚-ADP核糖聚合酶抑制剂在缺乏同源重组的乳腺癌治疗中的成功举例说明了综合性致死遗传相互作用在治疗由基因组不稳定性（3）驱动的乳腺癌中的效用。鉴于同源重组中的缺陷仅存在于乳腺癌的子集中，需要确定用于基因组不稳定性和有针对性的策略的额外驱动机制，以利用这些缺陷治疗癌症。在这里，我们表明中心耗尽诱导含有17 Q23扩增子的癌细胞中的合成致死性，其复发拷贝数像差，其定义了所有原发性乳腺癌肿瘤的约9％，并且与高水平的基因组不稳定性有关（4-6）。具体地，使用小分子的抑制马酚样激酶4（PLK4）导致中心耗尽，其触发了表现出对其特征的扩增的过表达的细胞中的有丝分裂灾难。为了解释这种效果，我们将Trim37识别为Centrosomal PericentRiolar材料的负调节剂。在17 Q23-缺乏中心粒子的扩增细胞中，TRIM37的增加水平嵌段患有脑血糖材料的焦化的形成 - 这些焦点是具有微管核的结构，其在没有CENTOSOMES的情况下成功细胞分裂所需的结构。最后，我们发现TRIM37的过表达通过在有丝分裂入口延迟Centosome成熟和分离来引起基因组不稳定性，从而增加有丝分裂误差的频率。总的来说，这些发现突出了TRIM37依赖性基因组不稳定性作为17 Q23扩增的乳腺癌的推定驾驶员事件，并提供用于使用中心体靶向治疗剂治疗这些癌症的理由。

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  • 来源
    《Nature》 |2020年第7825期|447-452|共6页
  • 作者

    Yeow Zhong Y.; Lambrus Bramwell G.; Marlow Rebecca; Zhan Kevin H.; Durin Mary-Anne; Evans Lauren T.; Scott Phillip M.; Thao Phan; Park Elizabeth; Ruiz Lorena A.; Moralli Daniela; Knight Eleanor G.; Badder Luned M.; Novo Daniela; Haider Syed; Green Catherine M.; Tutt Andrew N. J.; Lord Christopher J.; Chapman J. Ross; Holland Andrew J.;

  • 作者单位

    Univ Oxford Weatherall Inst Mol Med Mol Haematol Unit Med Res Council MRC Oxford England|Univ Oxford Wellcome Ctr Human Genet Oxford England;

    Johns Hopkins Univ Sch Med Dept Mol Biol & Genet Baltimore MD 21205 USA;

    Inst Canc Res Breast Canc Now Toby Robins Breast Canc Res Ctr London England|Kings Coll London Breast Canc Now Unit London England;

    Johns Hopkins Univ Sch Med Dept Mol Biol & Genet Baltimore MD 21205 USA;

    Univ Oxford Weatherall Inst Mol Med Mol Haematol Unit Med Res Council MRC Oxford England|Univ Oxford Wellcome Ctr Human Genet Oxford England;

    Johns Hopkins Univ Sch Med Dept Mol Biol & Genet Baltimore MD 21205 USA;

    Johns Hopkins Univ Sch Med Dept Mol Biol & Genet Baltimore MD 21205 USA;

    Johns Hopkins Univ Sch Med Dept Mol Biol & Genet Baltimore MD 21205 USA;

    Johns Hopkins Univ Sch Med Dept Mol Biol & Genet Baltimore MD 21205 USA;

    Johns Hopkins Univ Sch Med Dept Mol Biol & Genet Baltimore MD 21205 USA;

    Univ Oxford Wellcome Ctr Human Genet Oxford England;

    Inst Canc Res Breast Canc Now Toby Robins Breast Canc Res Ctr London England;

    Kings Coll London Breast Canc Now Unit London England;

    Inst Canc Res Breast Canc Now Toby Robins Breast Canc Res Ctr London England;

    Inst Canc Res Breast Canc Now Toby Robins Breast Canc Res Ctr London England;

    Univ Oxford Wellcome Ctr Human Genet Oxford England;

    Inst Canc Res Breast Canc Now Toby Robins Breast Canc Res Ctr London England|Kings Coll London Breast Canc Now Unit London England;

    Inst Canc Res Breast Canc Now Toby Robins Breast Canc Res Ctr London England;

    Univ Oxford Weatherall Inst Mol Med Mol Haematol Unit Med Res Council MRC Oxford England|Univ Oxford Wellcome Ctr Human Genet Oxford England;

    Johns Hopkins Univ Sch Med Dept Mol Biol & Genet Baltimore MD 21205 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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