Format

Send to

Choose Destination
Nat Commun. 2018 Mar 13;9(1):1044. doi: 10.1038/s41467-018-03283-z.

Integrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer.

Author information

1
Breast Cancer Now Research Unit, King's College London, London, SE1 9RT, UK.
2
School of Cancer and Pharmaceutical Sciences, King's Health Partners AHSC, Faculty of Life Sciences and Medicine, King's College London, London, WC2R 2LS, UK.
3
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK.
4
Cancer Bioinformatics, King's College London, London, SE1 9RT, UK.
5
Precision Immunology Cluster, Sanofi, 640 Memorial Drive, Cambridge, MA, 02149, USA.
6
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, SM2 5NG, UK.
7
Breast Cancer Now Research Unit, King's College London, London, SE1 9RT, UK. andrew.tutt@icr.ac.uk.
8
School of Cancer and Pharmaceutical Sciences, King's Health Partners AHSC, Faculty of Life Sciences and Medicine, King's College London, London, WC2R 2LS, UK. andrew.tutt@icr.ac.uk.
9
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK. andrew.tutt@icr.ac.uk.

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.

PMID:
29535384
PMCID:
PMC5849766
DOI:
10.1038/s41467-018-03283-z
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center