Abstract
PURPOSE: p12(CDK2-AP1) is a growth suppressor that negatively regulates cyclin-dependent kinase 2 (CDK2) activities and shows to interfere in DNA replication. Here, we aim to elucidate the role of p12(CDK2-AP1) in breast cancer progression. METHODS: Expression of p12(CDK2-AP1) protein was examined in 60 pairs of breast cancer specimens and adjacent non-tumor tissues using immunohistochemistry assay. Loss-of-function and gain-of-function analysis was performed on MCF-7 and MDA-MB-231 breast cancer cells. Routine assays including MTT, colony formation, flow cytometry, and tumorigenesis in nude mice were performed and cell cycle regulators were analyzed. RESULTS: p12(CDK2-AP1) was found to be significantly downregulated in 60 breast cancer tissues compared to corresponding non-tumorous tissues. The proliferation and colony formation ability was inhibited in cells that transduced with p12(CDK2-AP1) over-expression lentivirus, but enhanced in cells that transduced with p12(CDK2-AP1) RNAi lentivirus. p12(CDK2-AP1) over-expression led to G0/G1 phase arrest in the cell cycle and caused expression changes of cell cycle-related genes (CDK2, CDK4, p16(Ink4A), p21(Cip1/Waf1)). Furthermore, p12(CDK2-AP1) over-expression inhibited in vivo tumor growth in immunodeficiency mice, supporting an inhibitory role for p12(CDK2-AP1) in breast cancer development. CONCLUSIONS: As a cell cycle regulator, p12(CDK2-AP1) is involved in the development of breast cancer and maybe a potential therapeutic candidate to suppress tumorigenicity in breast cancer.