CDK12 Promotes Breast Cancer Progression and Maintains Stemness by Activating c-myc/β -catenin Signaling

Author(s): Fang Peng, Chuansheng Yang, Yanan Kong, Xiaojia Huang, Yanyu Chen, Yangfan Zhou, Xinhua Xie*, Peng Liu*.

Journal Name: Current Cancer Drug Targets

Volume 20 , Issue 2 , 2020

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Graphical Abstract:


Abstract:

Background: CDK12 is a promising therapeutic target in breast cancer with an effective ability of maintaining cancer cell stemness.

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. CDK12-altered breast cancer cell lines MDA-MB-231-shCDK12 and SkBr-3-CDK12 were then established. 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 the c-myc/β-catenin pathway.

Results: Our results showed a higher level of CDK12 exhibited in breast cancer samples. Tumor formation, cancer cell mobility, spheroid forming, and the epithelial-mesenchymal transition will be enhanced in the CDK12high group. In addition, CDK12 was associated with lung metastasis and maintained breast cancer cell stemness. CDK12high cancer cells presented higher tumorigenicity and a population of CD44+ subset compared with CDK12low cells. Our study demonstrated c-myc positively expressed with CDK12. The c-myc/β-catenin signaling was activated by CDK12, which is a potential mechanism to initiate breast cancer stem cell 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.

Keywords: Breast cancer, stemness, metastasis, CDK12, c-myc, β-catenin.

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VOLUME: 20
ISSUE: 2
Year: 2020
Page: [156 - 165]
Pages: 10
DOI: 10.2174/1568009619666191118113220
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