title: Phenotypic screening reveals topoisomerase I as a breast cancer stem cell therapeutic target.
abstract: Cancer stem cells (CSCs) are a subpopulation generally thought to be responsible for cancer initiation and progression. Because CSCs are often rare in the total tumor cell population and differentiate rapidly when grown in culture, it has been challenging to uncover compounds that selectively target CSCs. We previously described CSC-emulating cells derived from breast cancer cell lines that maintained a stable undifferentiated state. We optimized a phenotypic assay with these cells and screened 1,280-bioactive compounds, identifying five that preferentially inhibited CSC-like cell proliferation. Using a compound-guided target identification approach, we found high topoisomerase I (Topo I) expression levels in breast CSC-like cells and primary breast CSCs. Structurally unrelated small molecules targeting Topo I preferentially inhibited CSC-like cells. These results illustrate the substantial power of this CSC phenotypic screening platform and promote Topo I as a potential molecular therapeutic target for therapies aimed at expunging CSCs.
authors.affiliation: Section of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, The University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.forename: Kristi
authors.initials: K
authors.lastname: Rothermund
authors.forename: Sajithlal B
authors.initials: SB
authors.lastname: Gangadharan
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Edward V
authors.initials: EV
authors.lastname: Prochownik
authors.forename: John S
authors.initials: JS
authors.lastname: Lazo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D061986:MCF-7 Cells; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I