A Genome-wide RNAi Screen Reveals Essential Therapeutic Targets of Breast Cancer Stem Cells

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2019 Sep 3

PMID 31476112

Citations 20

Authors

Abir Arfaoui

Claire Rioualen

Violette Azzoni

Guillaume Pinna

Pascal Finetti

Julien Wicinski

Emmanuelle Josselin

Manon Macario

Remy Castellano

Candi Leonard-Stumpf

Anthony Bal

Abigaelle Gros

Sylvain Lossy

Maher Kharrat

Yves Collette

Francois Bertucci

Daniel Birnbaum

Hayet Douik

Ghislain Bidaut

Emmanuelle Charafe-Jauffret

Christophe Ginestier

Affiliations

Soon will be listed here.

Abstract

Therapeutic resistance is a major clinical challenge in oncology. Evidence identifies cancer stem cells (CSCs) as a driver of tumor evolution. Accordingly, the key stemness property unique to CSCs may represent a reservoir of therapeutic target to improve cancer treatment. Here, we carried out a genome-wide RNA interference screen to identify genes that regulate breast CSCs-fate (bCSC). Using an interactome/regulome analysis, we integrated screen results in a functional mapping of the CSC-related processes. This network analysis uncovered potential therapeutic targets controlling bCSC-fate. We tested a panel of 15 compounds targeting these regulators. We showed that mifepristone, salinomycin, and JQ1 represent the best anti-bCSC activity. A combination assay revealed a synergistic interaction of salinomycin/JQ1 association to deplete the bCSC population. Treatment of primary breast cancer xenografts with this combination reduced the tumor-initiating cell population and limited metastatic development. The clinical relevance of our findings was reinforced by an association between the expression of the bCSC-related networks and patient prognosis. Targeting bCSCs with salinomycin/JQ1 combination provides the basis for a new therapeutic approach in the treatment of breast cancer.

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