Show simple item record

dc.contributor.authorPatel, N
dc.contributor.authorWeekes, D
dc.contributor.authorDrosopoulos, K
dc.contributor.authorGazinska, P
dc.contributor.authorNoel, E
dc.contributor.authorRashid, M
dc.contributor.authorMirza, H
dc.contributor.authorQuist, J
dc.contributor.authorBrasó-Maristany, F
dc.contributor.authorMathew, S
dc.contributor.authorFerro, R
dc.contributor.authorPereira, AM
dc.contributor.authorPrince, C
dc.contributor.authorNoor, F
dc.contributor.authorFrancesch-Domenech, E
dc.contributor.authorMarlow, R
dc.contributor.authorde Rinaldis, E
dc.contributor.authorGrigoriadis, A
dc.contributor.authorLinardopoulos, S
dc.contributor.authorMarra, P
dc.contributor.authorTutt, ANJ
dc.date.accessioned2018-03-02T12:21:52Z
dc.date.issued2018-03-13
dc.identifier.citationNature communications, 2018, 9 (1), pp. 1044 - ?
dc.identifier.issn2041-1723
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1472
dc.identifier.eissn2041-1723
dc.identifier.doi10.1038/s41467-018-03283-z
dc.description.abstractTriple negative breast cancers (TNBCs) lack recurrent targetable driver mutations but demonstrate frequent copy number aberrations (CNAs). Here, we describe an integrative genomic and RNAi-based approach that identifies and validates gene addictions in TNBCs. CNAs and gene expression alterations are integrated and genes scored for pre-specified target features revealing 130 candidate genes. We test functional dependence on each of these genes using RNAi in breast cancer and non-malignant cells, validating malignant cell selective dependence upon 37 of 130 genes. Further analysis reveals a cluster of 13 TNBC addiction genes frequently co-upregulated that includes genes regulating cell cycle checkpoints, DNA damage response, and malignant cell selective mitotic genes. We validate the mechanism of addiction to a potential drug target: the mitotic kinesin family member C1 (KIFC1/HSET), essential for successful bipolar division of centrosome-amplified malignant cells and develop a potential selection biomarker to identify patients with tumors exhibiting centrosome amplification.
dc.formatElectronic
dc.format.extent1044 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectDNA Damage
dc.subjectKinesin
dc.subjectGene Expression Profiling
dc.subjectGenomics
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectGene Silencing
dc.subjectRNA Interference
dc.subjectFemale
dc.subjectDNA Copy Number Variations
dc.subjectCell Cycle Checkpoints
dc.subjectTriple Negative Breast Neoplasms
dc.titleIntegrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer.
dc.typeJournal Article
dcterms.dateAccepted2018-02-01
rioxxterms.versionofrecord10.1038/s41467-018-03283-z
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-03-13
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature communications
pubs.issue1
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/Drug Target Discovery
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/Drug Target Discovery
pubs.publication-statusPublished
pubs.volume9
pubs.embargo.termsNot known
icr.researchteamDrug Target Discoveryen_US
dc.contributor.icrauthorDrosopoulos, Konstantinosen
dc.contributor.icrauthorLinardopoulos, Spyridonen
dc.contributor.icrauthorTutt, Andrewen


Files in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record

https://creativecommons.org/licenses/by/4.0
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0