F. Peng, Chuansheng Yang, Y. Kong
Nov 17, 2019
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Quality indicators
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Current cancer drug targets
Abstract
BACKGROUND CDK12 is a promising therapeutic target in breast cancer with effective cancer cell stemness maintainess ability. OBJECTIVE We aim to investigate the mechanism of CDK12 in maintaining breast cancer stemness. METHODS CDK12 expression level was accessed by using RT-qPCR and IHC. Then we established CDK12-altered breast cancer cell lines MDA-MB-231-shCDK12 and SkBr-3-CDK12. CCK8, colony formation assays, and xenograft model were used to value the effect of CDK12 on tumorigenicity. Transwell assay, mammosphere formation , FACS, and lung metastasis model in vivo were determined. Western blot further characterized the mechanism of CDK12 in breast cancer stemness through c-myc/β-catenin pathway. RESULTS Our results showed higher level of CDK12 exhibited in breast cancer samples. Tumor formation, cancer cell mobility, spheroid forming, and epithelial-mesenchymal transition will be enhanced in the CDK12high group. In addition, CDK12 was associated with lung metastasis and maintained the breast cancer cells stemness. CDK12high cancer cells presented higher tumorigenicity and population of CD44+ subset compared with CDK12low cells. Our study demonstrated c-myc positively expressed with CDK12. The c-myc/β-catenin signaling was confirmed activating by CDK12, which is a potential mechanism to initiate the breast cancer stem cells renewal and may serve as a potential biomarker of breast cancer prognosis. CONCLUSION CDK12 overexpression promotes breast cancer tumorigenesis and maintains the stemness of breast cancer by activating c-myc/β-catenin signaling. Inhibiting CDK12 expression may become a potential therapy for breast cancer.