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 of TRIM37 . 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 highlight TRIM37- 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. TRIM37 overexpression 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.

中文翻译：

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靶向 17q23 扩增乳腺癌中 TRIM37 驱动的中心体功能障碍


基因组不稳定性是癌症的一个标志，在乳腺癌的发生和发展中起着核心作用 1 , 2 。聚 ADP 核糖聚合酶抑制剂在治疗同源重组缺陷型乳腺癌中的成功证明了合成致死性遗传相互作用在治疗由基因组不稳定性驱动的乳腺癌中的效用 3 。鉴于同源重组缺陷仅存在于乳腺癌的一个子集中，因此需要确定基因组不稳定的额外驱动机制以及在癌症治疗中利用这些缺陷的靶向策略。在这里，我们表明，中心体耗竭会诱导含有 17q23 扩增子的癌细胞产生合成致死性，这是一种反复出现的拷贝数畸变，约占所有原发性乳腺癌肿瘤的 9%，并且与高水平的基因组不稳定性相关 4 – 6 。具体来说，使用小分子抑制 Polo 样激酶 4 (PLK4) 会导致中心体耗竭，从而在表现出扩增子定向过度表达 TRIM37 的细胞中引发有丝分裂灾难。为了解释这种效应，我们将 TRIM37 确定为中心体周围物质的负调节因子。在缺乏中心体的 17q23 扩增细胞中，TRIM37 水平的增加会阻止包含中心粒周围物质的焦点的形成，这些焦点是具有微管成核能力的结构，是在没有中心体的情况下成功细胞分裂所必需的。最后，我们发现 TRIM37 的过度表达通过延迟有丝分裂进入时中心体的成熟和分离而导致基因组不稳定，从而增加有丝分裂错误的频率。 总的来说，这些发现强调 TRIM37 依赖性基因组不稳定性是 17q23 扩增乳腺癌中假定的驱动事件，并为使用中心体靶向治疗剂治疗这些癌症提供了理论基础。 TRIM37 过度表达会促进中心体功能障碍，从而导致含有重复 17q23 扩增子的乳腺癌细胞系的基因组不稳定，揭示了可以针对消除癌细胞的脆弱性。