Li Liping, Wang Hong, Yang Eddy S, Arteaga Carlos L, Xia Fen
Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Cancer Res. 2008 Nov 15;68(22):9141-6. doi: 10.1158/0008-5472.CAN-08-1127.
The epidermal growth factor receptor (EGFR) family has been implicated in several 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 gamma-H2AX foci, which is an in situ marker of chromosomal double-strand breaks. 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 show 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.
表皮生长因子受体（EGFR）家族与包括乳腺癌在内的多种癌症相关，其成员已成为新型癌症治疗的靶点。在本报告中，我们展示了强效EGFR抑制剂厄洛替尼、DNA损伤与人类乳腺癌细胞中的同源定向重组修复（HDR）之间的一种新联系。厄洛替尼抑制HDR。这并非继发于厄洛替尼介导的细胞周期变化，且与γ-H2AX焦点增加有关，γ-H2AX焦点是染色体双链断裂的原位标志物。Rad51和BRCA1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，厄洛替尼还会减弱DNA损伤诱导的Rad51焦点，并导致BRCA1在细胞质中滞留。由于BRCA1是一种穿梭蛋白，其促进HDR的核功能受其亚细胞定位控制，我们进一步表明，将BRCA1靶向转运至细胞质可增强厄洛替尼敏感性。这些发现提示了厄洛替尼通过其对BRCA1/HDR途径的作用而产生的一种新作用机制。此外，BRCA1/HDR状态可能是提高癌细胞对厄洛替尼敏感性的一条创新途径。
