Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer

Zhong Y. Yeow, Bramwell G. Lambrus, Rebecca Marlow, Kevin H. Zhan, Mary-Anne Durin, Lauren T. Evans, Phillip M. Scott, Thao Phan, Elizabeth Park, Lorena A. Ruiz, Daniela Moralli, Eleanor G. Knight, Luned M. Badder, Daniela Novo, Syed Haider, Catherine M. Green, Andrew N. J. Tutt, Christopher J. Lord, J. Ross Chapman () and Andrew J. Holland ()
Additional contact information
Zhong Y. Yeow: University of Oxford
Bramwell G. Lambrus: Johns Hopkins University School of Medicine
Rebecca Marlow: The Institute of Cancer Research
Kevin H. Zhan: Johns Hopkins University School of Medicine
Mary-Anne Durin: University of Oxford
Lauren T. Evans: Johns Hopkins University School of Medicine
Phillip M. Scott: Johns Hopkins University School of Medicine
Thao Phan: Johns Hopkins University School of Medicine
Elizabeth Park: Johns Hopkins University School of Medicine
Lorena A. Ruiz: Johns Hopkins University School of Medicine
Daniela Moralli: University of Oxford
Eleanor G. Knight: The Institute of Cancer Research
Luned M. Badder: The Breast Cancer Now Unit, King’s College London
Daniela Novo: The Institute of Cancer Research
Syed Haider: The Institute of Cancer Research
Catherine M. Green: University of Oxford
Andrew N. J. Tutt: The Institute of Cancer Research
Christopher J. Lord: The Institute of Cancer Research
J. Ross Chapman: University of Oxford
Andrew J. Holland: Johns Hopkins University School of Medicine

Nature, 2020, vol. 585, issue 7825, 447-452

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41586-020-2690-1

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