Loss of CtIP disturbs homologous recombination repair and sensitizes breast cancer cells to PARP inhibitors
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Junhui Wang1,2,*, Qianshan Ding3,*, Hiroaki Fujimori1,5, Akira Motegi4, Yoshio Miki2, Mitsuko Masutani1,5
1Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan
2Department of Molecular Genetics, Division of Medical Genomics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
3Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China
4Department of Radiation Genetics, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
5Department of Frontier Life Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
*These authors have contributed equally to this work
Mitsuko Masutani, e-mail: [email protected]
Keywords: CtIP, breast cancer, PARP inhibitors, 53BP1
Received: September 18, 2015 Accepted: November 27, 2015 Published: December 22, 2015
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.
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