Integrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer.
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Date
2018-03-13Author
Patel, N
Weekes, D
Drosopoulos, K
Gazinska, P
Noel, E
Rashid, M
Mirza, H
Quist, J
Brasó-Maristany, F
Mathew, S
Ferro, R
Pereira, AM
Prince, C
Noor, F
Francesch-Domenech, E
Marlow, R
de Rinaldis, E
Grigoriadis, A
Linardopoulos, S
Marra, P
Tutt, ANJ
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Humans
DNA Damage
Kinesin
Gene Expression Profiling
Genomics
Gene Expression Regulation, Neoplastic
Gene Silencing
RNA Interference
Female
DNA Copy Number Variations
Cell Cycle Checkpoints
Triple Negative Breast Neoplasms
Research team
Drug Target Discovery
Language
eng
Date accepted
2018-02-01
License start date
2018-03-13
Citation
Nature communications, 2018, 9 (1), pp. 1044 - ?
Publisher
NATURE PUBLISHING GROUP