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.
Highlights
Therapeutic resistance is a major clinical challenge in oncology
To define the genetic networks that govern breast CSCs-fate (bCSC) identity, we carried out a genome-wide RNAi screen using a siRNA pool library targeting ~18,000 human genes (4 pooled siRNAs/gene), in the SUM159 breast cancer cell line (BCL) (Fig 1A). siRNA pools were systematically tested as separate triplicates in an ALDEFLUORprobed bCSC detection assay (Fig 1B)
A gene was selected as a candidate when its silencing presented an absolute B-Score above or equal to 2.58 and an absolute fold change (FC) of bCSC proportion above or equal to 2 in reference to the negative control. siRNA pools designed to target ubiquitous cell survival genes, and that were found to induce a massive cell death (> 80%) of the whole cell population, were excluded from the analysis to focus on hit genes that alter the bCSC-fate (Fig 1C–E)
Summary
Evidence identifies cancer stem cells (CSCs) as a driver of tumor evolution. The key stemness property unique to CSCs may represent a reservoir of therapeutic target to improve cancer treatment. 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. Treatment of primary breast cancer xenografts with this combination reduced the tumor-initiating cell population and limited metastatic development. Targeting bCSCs with salinomycin/JQ1 combination provides the basis for a new therapeutic approach in the treatment of breast cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
