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dc.contributor.authorYeow, ZY
dc.contributor.authorLambrus, BG
dc.contributor.authorMarlow, R
dc.contributor.authorZhan, KH
dc.contributor.authorDurin, M-A
dc.contributor.authorEvans, LT
dc.contributor.authorScott, PM
dc.contributor.authorPhan, T
dc.contributor.authorPark, E
dc.contributor.authorRuiz, LA
dc.contributor.authorMoralli, D
dc.contributor.authorKnight, EG
dc.contributor.authorBadder, LM
dc.contributor.authorNovo, D
dc.contributor.authorHaider, S
dc.contributor.authorGreen, CM
dc.contributor.authorTutt, ANJ
dc.contributor.authorLord, CJ
dc.contributor.authorChapman, JR
dc.contributor.authorHolland, AJ
dc.date.accessioned2020-09-30T10:36:34Z
dc.date.issued2020-09-09
dc.identifier.citationNature, 2020, 585 (7825), pp. 447 - 452
dc.identifier.issn0028-0836
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4088
dc.identifier.eissn1476-4687
dc.identifier.doi10.1038/s41586-020-2690-1
dc.description.abstractGenomic 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.
dc.formatPrint-Electronic
dc.format.extent447 - 452
dc.languageeng
dc.language.isoeng
dc.subjectCell Line, Tumor
dc.subjectChromosomes, Human, Pair 17
dc.subjectCentrosome
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectGenomic Instability
dc.subjectUbiquitin-Protein Ligases
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectAntineoplastic Agents
dc.subjectMitosis
dc.subjectG2 Phase
dc.subjectFemale
dc.subjectTripartite Motif Proteins
dc.titleTargeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer.
dc.typeJournal Article
dcterms.dateAccepted2020-06-17
rioxxterms.versionofrecord10.1038/s41586-020-2690-1
rioxxterms.licenseref.startdate2020-09-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature
pubs.issue7825
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.publication-statusPublished
pubs.volume585
pubs.embargo.termsNot known
icr.researchteamGene Functionen_US
dc.contributor.icrauthorHaider, Syeden
dc.contributor.icrauthorLord, Christopheren
dc.contributor.icrauthorTutt, Andrewen


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