title: RAD51 Mediates Resistance of Cancer Stem Cells to PARP Inhibition in Triple-Negative Breast Cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Liu
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. suling@ustc.edu.cn mburness@med.umich.edu.
authors.forename: Monika L
authors.initials: ML
authors.lastname: Burness
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Rachel
authors.initials: R
authors.lastname: Martin-Trevino
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Joey
authors.initials: J
authors.lastname: Guy
authors.affiliation: Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Shoumin
authors.initials: S
authors.lastname: Bai
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Ramdane
authors.initials: R
authors.lastname: Harouaka
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Brooks
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Li
authors.initials: L
authors.lastname: Shang
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Alex
authors.initials: A
authors.lastname: Fox
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Tahra K
authors.initials: TK
authors.lastname: Luther
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: April
authors.initials: A
authors.lastname: Davis
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Trenton L
authors.initials: TL
authors.lastname: Baker
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Justin
authors.initials: J
authors.lastname: Colacino
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Shawn G
authors.initials: SG
authors.lastname: Clouthier
authors.affiliation: Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Shao
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Max S
authors.initials: MS
authors.lastname: Wicha
authors.affiliation: 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.
authors.forename: Suling
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage; D051135:Rad51 Recombinase / Q000235:genetics*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D051135:Rad51 Recombinase