dc.contributor.author | Patel, N | |
dc.contributor.author | Weekes, D | |
dc.contributor.author | Drosopoulos, K | |
dc.contributor.author | Gazinska, P | |
dc.contributor.author | Noel, E | |
dc.contributor.author | Rashid, M | |
dc.contributor.author | Mirza, H | |
dc.contributor.author | Quist, J | |
dc.contributor.author | Brasó-Maristany, F | |
dc.contributor.author | Mathew, S | |
dc.contributor.author | Ferro, R | |
dc.contributor.author | Pereira, AM | |
dc.contributor.author | Prince, C | |
dc.contributor.author | Noor, F | |
dc.contributor.author | Francesch-Domenech, E | |
dc.contributor.author | Marlow, R | |
dc.contributor.author | de Rinaldis, E | |
dc.contributor.author | Grigoriadis, A | |
dc.contributor.author | Linardopoulos, S | |
dc.contributor.author | Marra, P | |
dc.contributor.author | Tutt, ANJ | |
dc.date.accessioned | 2018-03-02T12:21:52Z | |
dc.date.issued | 2018-03-13 | |
dc.identifier.citation | Nature communications, 2018, 9 (1), pp. 1044 - ? | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/1472 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.doi | 10.1038/s41467-018-03283-z | |
dc.description.abstract | Triple 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.format | Electronic | |
dc.format.extent | 1044 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | DNA Damage | |
dc.subject | Kinesin | |
dc.subject | Gene Expression Profiling | |
dc.subject | Genomics | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Gene Silencing | |
dc.subject | RNA Interference | |
dc.subject | Female | |
dc.subject | DNA Copy Number Variations | |
dc.subject | Cell Cycle Checkpoints | |
dc.subject | Triple Negative Breast Neoplasms | |
dc.title | Integrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-02-01 | |
rioxxterms.versionofrecord | 10.1038/s41467-018-03283-z | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2018-03-13 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature communications | |
pubs.issue | 1 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 9 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Drug Target Discovery | |
dc.contributor.icrauthor | Drosopoulos, Konstantinos | |
dc.contributor.icrauthor | Linardopoulos, Spyridon | |
dc.contributor.icrauthor | Tutt, Andrew | |