Oncotarget

Research Papers:

Phenotypic Screening Reveals Topoisomerase I as a Breast Cancer Stem Cell Therapeutic Target

Fang Zhang, Kristi Rothermund, Sajithal B. Gangadharan, Yves Pommier, Edward V. Prochownik, John S. Lazo _

PDF  |  HTML  |  Supplementary Files  |  Order a Reprint

Oncotarget. 2012; 3:998-1010. https://doi.org/10.18632/oncotarget.632

Metrics: PDF 1433 views  |   HTML 1211 views  |   ?  


Abstract

Fang Zhang1, Kristi Rothermund1, Sajithlal B. Gangadharan1, Yves Pommier2, Edward V. Prochownik1, and John S. Lazo3

1 Section of Hematology/Oncology, Children’s Hospital of Pittsburgh of UPMC, The University of Pittsburgh, Pittsburgh, Pennsylvania

2 Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH

3 Department of Pharmacology and Chemistry, The University of Virginia, Charlottesville, Virginia

Correspondence:

John S. Lazo, email:

Keywords: cancer stem cell, Topoisomerase I, small molecule inhibitor, compound library screening

Received: August 24, 2012, Accepted: August 28, 2012, Published: August 31, 2012

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 632