Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer
| العنوان: | Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer |
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| المؤلفون: | Syed Haider, Luned M. Badder, Lorena A. Ruiz, Mary Anne Durin, Catherine M. Green, Bramwell G. Lambrus, J. Ross Chapman, Thao P. Phan, Lauren T Evans, Zhong Y. Yeow, Andrew J. Holland, Phillip M. Scott, Elizabeth M. Park, Daniela Novo, Eleanor Knight, Christopher J. Lord, Daniela Moralli, Andrew Tutt, Rebecca Marlow, Kevin H. Zhan |
| المصدر: | Nature. 585:447-452 |
| بيانات النشر: | Springer Science and Business Media LLC, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Genome instability, 0303 health sciences, Multidisciplinary, Cancer, Synthetic lethality, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Centrosome, Cancer cell, medicine, Cancer research, Mitotic catastrophe, 030217 neurology & neurosurgery, 030304 developmental biology, Pericentriolar material |
| الوصف: | Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer1,2. 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 instability3. 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 instability4–6. 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. |
| تدمد: | 1476-4687 0028-0836 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a75630a54aa646d8eec336fe8cae563e https://doi.org/10.1038/s41586-020-2690-1 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....a75630a54aa646d8eec336fe8cae563e |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14764687 00280836 |
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