title: Potentiated DNA Damage Response in Circulating Breast Tumor Cells Confers Resistance to Chemotherapy.
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.
authors.affiliation: From the Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, and.
authors.forename: Chang
authors.initials: C
authors.lastname: Gong
authors.affiliation: From the Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, and.
authors.forename: Bodu
authors.initials: B
authors.lastname: Liu
authors.affiliation: From the Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, and.
authors.forename: Yandan
authors.initials: Y
authors.lastname: Yao
authors.affiliation: From the Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, and.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Qu
authors.affiliation: From the Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, and.
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.affiliation: From the Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, and.
authors.forename: Weige
authors.initials: W
authors.lastname: Tan
authors.affiliation: From the Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, and.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China and.
authors.forename: Herui
authors.initials: H
authors.lastname: Yao
authors.affiliation: the Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Lee
authors.initials: L
authors.lastname: Zou
authors.affiliation: Breast Tumor Center, and fengxisu@vip.163.com.
authors.forename: Fengxi
authors.initials: F
authors.lastname: Su
authors.affiliation: From the Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, and songerwei02@aliyun.com.
authors.forename: Erwei
authors.initials: E
authors.lastname: Song
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating
chemical_list: D000970:Antineoplastic Agents
keywords: DNA damage; breast cancer; chemoresistance; circulating tumor cells; detachment; reactive oxygen species (ROS); tumor metastasis