Open AccessA genome‐wide RNA i screen reveals essential therapeutic targets of breast cancer stem cells
Author(s) -
Arfaoui Abir,
Rioualen Claire,
Azzoni Violette,
Pinna Guillaume,
Finetti Pascal,
Wicinski Julien,
Josselin Emmanuelle,
Macario Ma,
Castellano Rémy,
LéonardStumpf Candi,
Bal Anthony,
Gros Abigaelle,
Lossy Sylvain,
Kharrat Maher,
Collette Yves,
Bertucci Francois,
Birnbaum Daniel,
Douik Hayet,
Bidaut Ghislain,
CharafeJauffret Emmanuelle,
Ginestier Christophe
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201809930
Subject(s) - breast cancer , stem cell , rna , cancer stem cell , genome , biology , cancer , computational biology , cancer research , genetics , gene
Abstract Therapeutic resistance is a major clinical challenge in oncology. Evidence identifies cancer stem cells ( CSC s) as a driver of tumor evolution. Accordingly, the key stemness property unique to CSC s 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 CSC s‐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 JQ 1 represent the best anti‐ bCSC activity. A combination assay revealed a synergistic interaction of salinomycin/ JQ 1 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 bCSC s with salinomycin/ JQ 1 combination provides the basis for a new therapeutic approach in the treatment of breast cancer.