Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China.
Department of Head-Neck and Breast Surgery, Yuebei People's Hospital of Shantou University, Shaoguan, Guangdong, China.
Curr Cancer Drug Targets. 2020;20(2):156-165. doi: 10.2174/1568009619666191118113220.
CDK12 is a promising therapeutic target in breast cancer with an effective ability of maintaining cancer cell stemness.
We aim to investigate the mechanism of CDK12 in maintaining breast cancer stemness.
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.
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.
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.
CDK12 是乳腺癌中一种有前景的治疗靶点，具有维持癌细胞干性的有效能力。
我们旨在研究 CDK12 维持乳腺癌干性的机制。
通过 RT-qPCR 和 IHC 评估 CDK12 的表达水平。然后建立 CDK12 改变的乳腺癌细胞系 MDA-MB-231-shCDK12 和 SkBr-3-CDK12。使用 CCK8、集落形成实验和异种移植模型来评估 CDK12 对肿瘤发生的影响。通过 Transwell 实验、类器官形成、FACS 和体内肺转移模型来确定。Western blot 进一步通过 c-myc/β-catenin 通路来描述 CDK12 在乳腺癌干性中的作用机制。
我们的结果表明 CDK12 在乳腺癌样本中表达水平较高。在 CDK12high 组中，肿瘤形成、癌细胞迁移、球体形成和上皮-间充质转化将增强。此外，CDK12 与肺转移有关，并维持乳腺癌细胞干性。与 CDK12low 细胞相比，CDK12high 癌细胞表现出更高的肿瘤发生能力和 CD44+亚群。我们的研究表明 c-myc 与 CDK12 呈正相关表达。CDK12 激活 c-myc/β-catenin 信号通路，这是启动乳腺癌干细胞更新的潜在机制，可作为乳腺癌预后的潜在标志物。
CDK12 过表达通过激活 c-myc/β-catenin 信号通路促进乳腺癌肿瘤发生和维持乳腺癌干性。抑制 CDK12 表达可能成为乳腺癌的潜在治疗方法。
