Gong Chang, Liu Bodu, Yao Yandan, Qu Shaohua, Luo Wei, Tan Weige, Liu Qiang, Yao Herui, Zou Lee, Su Fengxi, Song Erwei
From the Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, and.
Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China and.
J Biol Chem. 2015 Jun 12;290(24):14811-25. doi: 10.1074/jbc.M115.652628. Epub 2015 Apr 20.
Circulating tumor cells (CTCs) are seeds for cancer metastasis and are predictive of poor prognosis in breast cancer patients. Whether CTCs and primary tumor cells (PTCs) respond to chemotherapy differently is not known. Here, we show that CTCs of breast cancer are more resistant to chemotherapy than PTCs because of potentiated DNA repair. Surprisingly, the chemoresistance of CTCs was recapitulated in PTCs when they were detached from the extracellular matrix. Detachment of PTCs increased the levels of reactive oxygen species and partially activated the DNA damage checkpoint, converting PTCs to a CTC-like state. Inhibition of checkpoint kinases Chk1 and Chk2 in CTCs reduces the basal checkpoint response and sensitizes CTCs to DNA damage in vitro and in mouse xenografts. Our results suggest that DNA damage checkpoint inhibitors may benefit the chemotherapy of breast cancer patients by suppressing the chemoresistance of CTCs and reducing the risk of cancer metastasis.
循环肿瘤细胞（CTCs）是癌症转移的种子，可预测乳腺癌患者的不良预后。目前尚不清楚CTCs与原发性肿瘤细胞（PTCs）对化疗的反应是否不同。在此，我们表明，由于DNA修复增强，乳腺癌的CTCs比PTCs对化疗更具抗性。令人惊讶的是，当PTCs与细胞外基质分离时，其在PTCs中重现了CTCs的化学抗性。PTCs的分离增加了活性氧水平并部分激活了DNA损伤检查点，将PTCs转变为类似CTC的状态。在CTCs中抑制检查点激酶Chk1和Chk2可降低基础检查点反应，并使CTCs在体外和小鼠异种移植中对DNA损伤敏感。我们的结果表明，DNA损伤检查点抑制剂可能通过抑制CTCs的化学抗性和降低癌症转移风险而使乳腺癌患者从化疗中受益。
