Loss of CtIP disturbs homologous recombination repair and sensitizes breast cancer cells to PARP inhibitors.
Loss of CtIP disturbs homologous recombination repair and sensitizes breast cancer cells to PARP inhibitors.
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DOI：
10.18632/oncotarget.6715
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发表时间：
2016-02-16
期刊：
影响因子：
--
通讯作者：
Masutani M
中科院分区：
文献类型：
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作者：
Wang J;Ding Q;Fujimori H;Motegi A;Miki Y;Masutani M
乳腺癌是全世界死亡的主要原因之一，因此，迫切需要用于治疗乳腺癌的新的和改进的方法。CtIP（RBBP 8）是一种多功能蛋白，参与多种细胞功能，包括转录、DNA复制、DNA修复和G1和G2细胞周期检查点。CtIP通过与肿瘤抑制蛋白BRCA 1相互作用，在同源重组修复中发挥重要作用。在这里，我们分析了CtIP的表达谱数据挖掘使用已发表的微阵列数据集。我们发现CtIP表达在乳腺癌患者中经常降低，并且低表达CtIP mRNA的患者组与显著较低的生存率相关。乳腺癌MCF 7细胞中CtIP的敲低减少了Rad 51灶的数量，并增强了f-照射后的fH 2AX灶的形成，表明CtIP的缺乏减少了同源重组修复并延迟了DNA双链断裂修复。为了探索CtIP对PARP抑制剂治疗乳腺癌的作用，用PARP抑制剂奥拉帕尼（AZD 2281）或维利帕尼（ABT-888）处理CtIP耗尽的MCF 7细胞。与BRCA突变细胞一样，PARP抑制剂通过阻止细胞修复DNA损伤，导致细胞活力降低，对CtIP耗尽的细胞显示出细胞毒性。此外，具有MCF 7细胞的小鼠中的异种移植肿瘤模型证明在CtIP缺乏下对PARP抑制的敏感性显著增加。总之，本研究表明，CtIP表达水平低与乳腺癌预后不良相关，并为将CtIP表达确立为PARP抑制剂反应的生物标志物提供了依据，因此为重要的患者亚组提供了新的治疗选择。
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.