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Clin Cancer Res. 2017 Jan 15;23(2):514-522. doi: 10.1158/1078-0432.CCR-15-1348. Epub 2016 Dec 29.

RAD51 Mediates Resistance of Cancer Stem Cells to PARP Inhibition in Triple-Negative Breast Cancer.

Author information

1
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
2
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. suling@ustc.edu.cn mburness@med.umich.edu.
3
Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
4
Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
5
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
6
Innovation Center for Cell Signaling Network and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei, China. suling@ustc.edu.cn mburness@med.umich.edu.

Abstract

INTRODUCTION:

PARP inhibitors have shown promising results in early studies for treatment of breast cancer susceptibility gene (BRCA)-deficient breast cancers; however, resistance ultimately develops. Furthermore, the benefit of PARP inhibitors (PARPi) in triple-negative breast cancers (TNBC) remains unknown. Recent evidence indicates that in TNBCs, cells that display "cancer stem cell" properties are resistant to conventional treatments, mediate tumor metastasis, and contribute to recurrence. The sensitivity of breast cancer stem cells (CSC) to PARPi is unknown.

EXPERIMENTAL DESIGN:

We determined the sensitivity of breast CSCs to PARP inhibition in BRCA1-mutant and -wild-type TNBC cell lines and tumor xenografts. We also investigated the role of RAD51 in mediating CSC resistance to PARPi in these in vitro and in vivo models.

RESULTS:

We demonstrated that the CSCs in BRCA1-mutant TNBCs were resistant to PARP inhibition, and that these cells had both elevated RAD51 protein levels and activity. Downregulation of RAD51 by shRNA sensitized CSCs to PARP inhibition and reduced tumor growth. BRCA1-wild-type cells were relatively resistant to PARP inhibition alone, but reduction of RAD51 sensitized both CSC and bulk cells in these tumors to PARPi treatment.

CONCLUSIONS:

Our data suggest that in both BRCA1-mutant and BRCA1-wild-type TNBCs, CSCs are relatively resistant to PARP inhibition. This resistance is mediated by RAD51, suggesting that strategies aimed at targeting RAD51 may increase the therapeutic efficacy of PARPi. Clin Cancer Res; 23(2); 514-22. ©2016 AACR.

PMID:
28034904
DOI:
10.1158/1078-0432.CCR-15-1348
[Indexed for MEDLINE]
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