Potentiated DNA Damage Response in Circulating Breast Tumor Cells Confers Resistance to Chemotherapy |
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| Authors: | Chang Gong Bodu Liu Yandan Yao Shaohua Qu Wei Luo Weige Tan Qiang Liu Herui Yao Lee Zou Fengxi Su Erwei Song |
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| Affiliation: | 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 ;the ‖Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129 |
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| Abstract: | 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. |
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| Keywords: | breast cancer chemoresistance DNA damage reactive oxygen species (ROS) tumor metastasis circulating tumor cells detachment |
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