TY - JOUR
T1 - Integrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer
AU - Patel, Nirmesh
AU - Weekes, Daniel
AU - Drosopoulos, Konstantinos
AU - Gazinska, Patrycja
AU - Noel, Elodie
AU - Rashid, Mamun
AU - Mirza, Hasan
AU - Quist, Jelmar
AU - Brasó-Maristany, Fara
AU - Mathew, Sumi
AU - Ferro, Riccardo
AU - Pereira, Ana Mendes
AU - Prince, Cynthia
AU - Noor, Farzana
AU - Francesch-Domenech, Erika
AU - Marlow, Rebecca
AU - de Rinaldis, Emanuele
AU - Grigoriadis, Anita
AU - Linardopoulos, Spiros
AU - Marra, Pierfrancesco
AU - Tutt, Andrew N J
PY - 2018/3/13
Y1 - 2018/3/13
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1038/s41467-018-03283-z
DO - 10.1038/s41467-018-03283-z
M3 - Article
C2 - 29535384
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1044
ER -
