CDK16 is a vulnerable target for triple negative breast cancer therapy

ABSTRACT: Background: CDK16 is an atypical PCTAIRE kinase, and its activity is dependent on Cyclin Y (CCNY) family. CCNYs have been reported to regulate mammary stem cell activity and mammary gland development, and CCNY plays an oncogenic role in a variety of cancers including breast cancer. However, whether CDK16 plays a role in breast cancer and whether CDK16 can be served as a therapeutic target for breast cancer remains unknown. Methods: TCGA/GEO database analysis and KM survival analysis were used to examine the mRNA expression and the clinical relevance of PFTAIRE and PCTAIRE kinases in breast cancer. The expression of CDK16 protein was determined by CPTAC dataset output and immunohistochemical analysis of breast cancer tissue microarray and immunoblot analysis of additional clinical samples. Knockdown and overexpression of CDK16 were mediated by shRNA and lentivirus vectors, respectively. Cell proliferation was assessed by colony formation and MTT analysis. The cell cycle and apoptosis were examined by FACS analysis. Wound-healing and trans-well invasion assay were conducted to test cell migration ability. The functions of CDK16 on tumorigenesis and metastasis were evaluated by cell line-derived xenograft, patient-derived organoid/xenograft, lung metastasis and systemic metastasis mouse models. RNA-sequencing analysis was performed to reveal the potential molecular mechanisms involved in the function of CDK16. Pharmacological inhibition of CDK16 was achieved by its inhibitor Rebastinib to further assess the anti-tumor effect of targeting CDK16. Results: CDK16 is highly expressed in breast cancer, especially in triple-negative breast cancer (TNBC). The elevated CDK16 expression is correlated with poor outcomes in breast cancer patients. CDK16 promotes the proliferation and migration of TNBC cells in vitro and tumorigenesis and metastasis of TNBC tumors in vivo. Both gene knockdown and pharmacological inhibition of CDK16 significantly repress tumor progression of TNBC. Mechanically, CDK16 not only regulates spindle formation by phosphorylating PRC1 at the T481 site, but also regulates the Rb-E2F pathway by phosphorylating Rb, which are essential for cell cycle progression and cell proliferation of tumor cells. Conclusion: CDK16 plays an oncogenic role in TNBC and can be served as a novel potential therapeutic target for TNBC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189758 | GEO | 2021/12/03

REPOSITORIES: GEO