title: 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.
authors.affiliation: Department of Pathology, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Feng
authors.forename: Zhaojia
authors.initials: Z
authors.lastname: Wu
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Wu
authors.forename: William
authors.initials: W
authors.lastname: Hankey
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Prior
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ganju
authors.forename: Rulong
authors.initials: R
authors.lastname: Shen
authors.forename: Xianghong
authors.initials: X
authors.lastname: Zou
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases / Q000502:physiology*
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1