Journal
EMBO MOLECULAR MEDICINE
Volume 11, Issue 10, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201809930
Keywords
breast cancer; cancer stem cells; JQ1; RNAi screen; salinomycin
Categories
Funding
- Inserm
- Institut Paoli-Calmettes
- INCa [INCa_5911]
- SIRIC Marseille [INCa-DGOS-Inserm 6038]
- Ligue National Contre le Cancer (Label DB)
- Ligue National Contre le Cancer
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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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