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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Checkpoints / genetics
  • DNA Copy Number Variations / genetics
  • DNA Damage / genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Silencing / physiology
  • Genomics / methods*
  • Humans
  • Kinesin / genetics
  • RNA Interference
  • Triple Negative Breast Neoplasms / genetics*

Substances

  • human spleen, embryo, and testes expressed protein, human
  • Kinesin