Phenotypic screening reveals topoisomerase I as a breast cancer stem cell therapeutic target

Area of Science:

• Oncology
• Cell Biology
• Pharmacology

Background:

• Cancer stem cells (CSCs) drive tumor initiation and progression.
• Targeting CSCs is challenging due to their rarity and rapid differentiation in vitro.
• Previous work established stable, CSC-emulating breast cancer cell lines.

Purpose of the Study:

• To develop and utilize a phenotypic screening platform to identify compounds selectively targeting CSCs.
• To identify the molecular targets of compounds that inhibit CSC-like cell proliferation.
• To evaluate topoisomerase I (Topo I) as a potential therapeutic target for CSCs.

Main Methods:

• Phenotypic screening of 1,280 bioactive compounds using CSC-emulating cells.
• Compound-guided target identification.
• Analysis of Topoisomerase I (Topo I) expression in CSC-like cells and primary CSCs.
• Testing of Topo I-targeting small molecules for selective inhibition of CSC-like cells.

Main Results:

• Five compounds were identified that preferentially inhibited CSC-like cell proliferation.
• High Topoisomerase I (Topo I) expression was observed in CSC-like cells and primary breast CSCs.
• Structurally diverse small molecules targeting Topo I demonstrated preferential inhibition of CSC-like cells.

Conclusions:

• The CSC phenotypic screening platform is powerful for identifying CSC-targeting compounds.
• Topoisomerase I (Topo I) is a promising molecular target for therapies aimed at eliminating CSCs.
• Targeting Topo I may offer a novel therapeutic strategy for breast cancer treatment.