A genome-wide RNAi screen reveals essential therapeutic targets of breast cancer stem cells.
JQ1
RNAi screen
breast cancer
cancer stem cells
salinomycin
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
13
10
2018
revised:
13
07
2019
accepted:
07
08
2019
pubmed:
3
9
2019
medline:
17
4
2020
entrez:
3
9
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31476112
doi: 10.15252/emmm.201809930
pmc: PMC6783652
doi:
Substances chimiques
Antineoplastic Agents
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e9930Subventions
Organisme : Institut National Du Cancer (INCa)
ID : INCa_5911
Pays : International
Organisme : Institut National Du Cancer (INCa)
ID : INCa-DGOS-Inserm 6038
Pays : International
Organisme : Ligue Contre le Cancer (Label DB)
Pays : International
Informations de copyright
© 2019 The Authors. Published under the terms of the CC BY 4.0 license.
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