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.Breast cancer is one of the leading causes of morbidity and mortality in women worldwide (10,30,37). The majority of breast cancer deaths result from metastasis of breast cancer to other organs (14,16,36). Breast cancer metastasis has been shown to reduce the chances of long-term survival from 90% to around 5% (22). Therefore, insight into the molecular mechanisms underlying breast cancer invasion and metastasis would enable more effective treatment for breast cancer.Cdc25 phosphatases (Cdc25A, Cdc25B, and Cdc25C) promote cell cycle progression by dephosphorylating and activating cyclin-dependent kinases (Cdks) (38). Cdc25A activates cyclin E (A)-Cdk2 during G 1 through S and also seems to be involved in activation of Cdk1 at the G 2 /M boundary, and Cdc25A plays a nonredundant role in embryogenesis and oncogenesis (4, 12, 28). Cdc25B and Cdc25C, which collaborate for activation of cyclin B-Cdk1 at the G 2 /M boundary, are dispensable for checkpoint function (11,18,34). Among the Cdc25 family, Cdc25A is highlighted as an indispensable regulator of cell development and a driver of tumorigenesis (12,28,43,55). While the known role of Cdc25A in cell cycle progression and proliferation has been studied with respect to breast cancer pathogenesis (12,20,28,43), little is understood about whether and how Cdc25A affects the metastatic potential of breast cancer cells. Although epidemiologic studies have shown that most breast cancer patients (50 to 69%) have overexpressed Cdc25A and show poor prognosis (8, 25), not much is known about its association with breast cancer metastasis. In this study, we show that Cdc25A overexpression is correlated with the metastatic phenotype in breast cancer patient samples.Foxo1, one of the mammalian Forkhead transcription factors of class O (FoxO), is involved in a wide range of biological processes (2, 24). The Foxo1...

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

“…Of interest, miR-20a was identified as being overexpressed in the transition from colon mucosa to early adenoma, and was predicted to target multiple WNT pathway genes (Bartley et al 2011). The observation according to which CCAT2-enhanced invasion is mediated by MYC-regulated miRNAs and also possibly by other pro-metastatic targets such as CDC25A (Feng et al 2011), rather than by MYC itself, suggests a complex regulatory network that needs to be further explored in the future. This is also in agreement with the recent observation by The Cancer Genome Atlas (TCGA) Consortium that MYC-driven transcriptional activation and repression play important roles in colon cancer (The Cancer Genome Atlas Network 2012).…”

Liver X Receptor a Inhibits Osteosarcoma Cell Proliferation through Up-Regulation of FoxO1

“…At the molecular level, FoxO1 could up-regulate the cell-cycle inhibitors p21 and p27, while down-regulate the cell cycle regulator cyclinD1/2, consequently leading to G1/S cell-cycle arrest [18]. Indeed, FoxO1 expression or activity was reduced in several types of cancers, including gastric cancer, breast cancer and osteosarcoma [19,20,21,22,23]. …”

The regulatory roles of phosphatases in cancer

“…Recent studies have demonstrated increased Fox1 activity following CDC25A-indcued dephosphorylation of CDK2. Inhibition of CDC25A inhibits metastases in BC mouse models, suggesting that this phosphatase may be a potential target for advanced stages of the disease (248).CDC25B is overexpressed in primary BC tumours (249), although expression levels do not always correlate with an aggressive phenotype (250).…”