Erlotinib attenuates homologous recombinational repair of chromosomal breaks in human breast cancer cells.
Erlotinib attenuates homologous recombinational repair of chromosomal breaks in human breast cancer cells.
复制标题
厄洛替尼可减轻人类乳腺癌细胞中染色体断裂的同源重组修复。
DOI：
10.1158/0008-5472.can-08-1127
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Xia, Fen
中科院分区：
文献类型：
--
作者：
Li, Liping;Wang, Hong;Yang, Eddy S.;Arteaga, Carlos L.;Xia, Fen
表皮生长因子受体家族（EGFR）与包括乳腺癌在内的多种癌症有关，其成员已成为新型癌症治疗的靶点。在这份报告中，我们展示了一种新的联系埃罗替尼，一种有效的EGFR抑制剂，DNA损伤，和同源定向重组修复（HDR）在人类乳腺癌细胞。厄洛替尼抑制HDR。这不是继发于厄洛替尼介导的细胞周期变化，而是与γ-H2 AX灶增加相关，γ-H2 AX灶是染色体双链断裂（DSB）的原位标志物。Rad 51和BRCA 1都是HDR机制的重要组成部分。与厄洛替尼处理的细胞中HDR降低一致，厄洛替尼也减弱DNA损伤诱导的Rad 51病灶，并导致BRCA 1的细胞质滞留。由于BRCA 1是一种穿梭蛋白，其促进HDR的核功能由其亚细胞定位控制，我们进一步证明BRCA 1靶向易位到细胞质增强了厄洛替尼的敏感性。这些发现表明厄洛替尼通过其对BRCA 1/HDR通路的作用而具有新的作用机制。此外，BRCA 1/HDR状态可能是增强癌细胞对厄洛替尼敏感性的创新途径。
The epidermal growth factor receptor family (EGFR) has been implicated in a number of cancers, including breast, and its members have become the target of novel cancer therapies. In this report, we show a novel link between erlotinib, a potent EGFR inhibitor, DNA damage, and homology-directed recombinational repair (HDR) in human breast cancer cells. Erlotinib suppresses HDR. This is not secondary to erlotinib-mediated changes in cell cycle and is associated with increased γ-H2AX foci, which is an in situ marker of chromosomal double strand breaks (DSBs). Both Rad51 and BRCA1 are essential components of the HDR machinery. Consistent with decreased HDR in erlotinib-treated cells, erlotinib also attenuates DNA damage-induced Rad51 foci and results in cytoplasmic retention of BRCA1. As BRCA1 is a shuttling protein and its nuclear function of promoting HDR is controlled by its subcellular localization, we further demonstrate that targeted translocation of BRCA1 to the cytoplasm enhances erlotinib sensitivity. These findings suggest a novel mechanism of action of erlotinib through its effects on the BRCA1/HDR pathway. Furthermore, BRCA1/HDR status may be an innovative avenue to enhance the sensitivity of cancer cells to erlotinib.