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

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.

SUBMITTER: Patel N

PROVIDER: S-EPMC5849766 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Patel Nirmesh N Weekes Daniel D Drosopoulos Konstantinos K Gazinska Patrycja P Noel Elodie E Rashid Mamun M Mirza Hasan H Quist Jelmar J Brasó-Maristany Fara F Mathew Sumi S Ferro Riccardo R Pereira Ana Mendes AM Prince Cynthia C Noor Farzana F Francesch-Domenech Erika E Marlow Rebecca R de Rinaldis Emanuele E Grigoriadis Anita A Linardopoulos Spiros S Marra Pierfrancesco P Tutt Andrew N J ANJ

Nature communications 20180313 1

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, ...[more]

PMID: 29535384

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

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

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