title: Loss of CtIP disturbs homologous recombination repair and sensitizes breast cancer cells to PARP inhibitors.
abstract: Breast cancer is one of the leading causes of death worldwide, and therefore, new and improved approaches for the treatment of breast cancer are desperately needed. CtIP (RBBP8) is a multifunctional protein that is involved in various cellular functions, including transcription, DNA replication, DNA repair and the G1 and G2 cell cycle checkpoints. CtIP plays an important role in homologous recombination repair by interacting with tumor suppressor protein BRCA1. Here, we analyzed the expression profile of CtIP by data mining using published microarray data sets. We found that CtIP expression is frequently decreased in breast cancer patients, and the patient group with low-expressing CtIP mRNA is associated with a significantly lower survival rate. The knockdown of CtIP in breast cancer MCF7 cells reduced Rad51 foci numbers and enhanced f H2AX foci formation after f-irradiation, suggesting that deficiency of CtIP decreases homologous recombination repair and delays DNA double strand break repair. To explore the effect of CtIP on PARP inhibitor therapy for breast cancer, CtIP-depleted MCF7 cells were treated with PARP inhibitor olaparib (AZD2281) or veliparib (ABT-888). As in BRCA mutated cells, PARP inhibitors showed cytotoxicity to CtIP-depleted cells by preventing cells from repairing DNA damage, leading to decreased cell viability. Further, a xenograft tumor model in mice with MCF7 cells demonstrated significantly increased sensitivity towards PARP inhibition under CtIP deficiency. In summary, this study shows that low level of CtIP expression is associated with poor prognosis in breast cancer, and provides a rationale for establishing CtIP expression as a biomarker of PARP inhibitor response, and consequently offers novel therapeutic options for a significant subset of patients.
authors.affiliation: Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan.|Department of Molecular Genetics, Division of Medical Genomics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Junhui
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Qianshan
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan.|Department of Frontier Life Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fujimori
authors.affiliation: Department of Radiation Genetics, Kyoto University Graduate School of Medicine, Kyoto 606-8501 Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Motegi
authors.affiliation: Department of Molecular Genetics, Division of Medical Genomics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Miki
authors.affiliation: Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan.|Department of Frontier Life Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Masutani
mesh_terms: D000818:Animals; D017209:Apoptosis; D019313:BRCA1 Protein / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004706:Endodeoxyribonucleases; D005260:Female; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D060787:Neoplasm Grading; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011379:Prognosis; D059767:Recombinational DNA Repair / Q000235:genetics*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human
keywords: 53BP1; CtIP; PARP inhibitors; breast cancer