Cdc25A Regulates Matrix Metalloprotease 1 through Foxo1 and Mediates Metastasis of Breast Cancer Cells

Abstract

Cdc25A is a cell cycle-activating phosphatase, and its overexpression in breast cancers has been shown to correlate with poor prognosis. Most recent studies related to Cdc25A and tumor progression have focused on its role in regulating cell cycle progression. However, less is known about how Cdc25A modulates the metastasis of breast cancer cells. In this study, we revealed that Cdc25A enhances Foxo1 stability by dephosphorylating Cdk2, and Foxo1 was shown to directly regulate transcription of the metastatic factor MMP1. Further studies have shown that overexpression of Cdc25A in breast cancer cells enhances metastasis, whereas its downmodulation inhibits metastasis in mouse models, and the effects of Cdc25A on breast cancer cell metastasis are independent of cell proliferation and apoptosis. Furthermore, we have demonstrated that aberrant Cdc25A in breast cancer patient samples directly correlates with the metastatic phenotype. Further insights into this critical role of Cdc25A in the metastasis of breast cancer cells and the trial of an anti-Cdc25A strategy in mouse models may reveal its therapeutic potential in prevention and treatment of breast cancer cell dissemination.

ACKNOWLEDGMENTS

We thank H. Huang for Cdk2-related plasmids, A. Bonni and S. Guo for kindly providing Foxo1 and Foxo-1-S249A-GFP plasmids, S. H. Barsky for the Mary-X cell line, G. L. Wang, and Y. Jin for help in plasmid construction, bioinformatics, and promoter analysis, and Michelle Smith, Weiwei Zhang, Yuanzhi Lu, and Legong Li for helpful suggestions.

This research was supported by grants NIH R01 CA113579 (X.Z.), NSFC 30571006 and 30671026 (X.Z.), KM200810028011 (X.Z.), and NIH R01 CA109527 (R.K.G.) in part.