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.

[1]  P. Dhawan,et al.  A novel NF-kappa B-inducing kinase-MAPK signaling pathway up-regulates NF-kappa B activity in melanoma cells. , 2002, The Journal of biological chemistry.

[2]  H. Piwnica-Worms,et al.  Absence of Apparent Phenotype in Mice Lacking Cdc25C Protein Phosphatase , 2001, Molecular and Cellular Biology.

[3]  H. Kiyokawa,et al.  The Cell Cycle-Regulatory CDC25A Phosphatase Inhibits Apoptosis Signal-Regulating Kinase 1 , 2001, Molecular and Cellular Biology.

[4]  Zhiwei Wang,et al.  Therapeutic intervention of experimental breast cancer bone metastasis by indole-3-carbinol in SCID-human mouse model , 2006, Molecular Cancer Therapeutics.

[5]  D. Nimbalkar,et al.  Transforming Growth Factor β Facilitates β-TrCP-Mediated Degradation of Cdc25A in a Smad3-Dependent Manner , 2005, Molecular and Cellular Biology.

[6]  Michele Pagano,et al.  Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage. , 2003, Nature.

[7]  郑俊.  Maintenance , 2002, The Islamic Law of Personal Status.

[8]  J. Ludlow,et al.  Hypoxia arrests ovarian carcinoma cell cycle progression, but invasion is unaffected. , 1996, Cancer research.

[9]  L. Tessarollo,et al.  Cdc25b phosphatase is required for resumption of meiosis during oocyte maturation , 2002, Nature Genetics.

[10]  D. Tindall,et al.  Dynamic FoxO transcription factors , 2007, Journal of Cell Science.

[11]  A. Fukamizu,et al.  Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. , 2008, Molecular cell.

[12]  R. Weinberg,et al.  Tumour invasion and metastasis initiated by microRNA-10b in breast cancer , 2007, Nature.

[13]  W. Gerald,et al.  Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. , 2005, The Journal of clinical investigation.

[14]  I. Poola,et al.  Identification of MMP-1 as a putative breast cancer predictive marker by global gene expression analysis , 2005, Nature Medicine.

[15]  E. Schleicher,et al.  Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB. , 2008, Carcinogenesis.

[16]  Ajit Varki,et al.  Molecular basis of metastasis. , 2009, The New England journal of medicine.

[17]  M. Tada,et al.  High MMP-1 mRNA expression is a risk factor for disease-free and overall survivals in patients with invasive breast carcinoma. , 2008, The Journal of surgical research.

[18]  A. Miyauchi,et al.  Expression of cdc25A and cdc25B phosphatase in breast carcinoma , 2004, Breast cancer.

[19]  P. Dhawan,et al.  Correction: A Novel NF-κB-inducing Kinase-MAPK Signaling Pathway Up-regulates NF-κB Activity in Melanoma Cells , 2001, The Journal of Biological Chemistry.

[20]  S. Zucker,et al.  Membrane Type 1 Matrix Metalloproteinase Induces Epithelial-to-Mesenchymal Transition in Prostate Cancer* , 2008, Journal of Biological Chemistry.

[21]  D. Beach,et al.  Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: Evidence for multiple roles of mitotic cyclins , 1991, Cell.

[22]  H. Piwnica-Worms,et al.  Normal Cell Cycle and Checkpoint Responses in Mice and Cells Lacking Cdc25B and Cdc25C Protein Phosphatases , 2005, Molecular and Cellular Biology.

[23]  M. Loda,et al.  CDC25 phosphatases as potential human oncogenes. , 1995, Science.

[24]  Florian Kronenberg,et al.  Matrix Metalloproteinase 1 (MMP1) Is Associated with Early-Onset Lung Cancer , 2008, Cancer Epidemiology Biomarkers & Prevention.

[25]  Esther B. E. Becker,et al.  Activation of FOXO1 by Cdk1 in Cycling Cells and Postmitotic Neurons , 2008, Science.

[26]  B. Burgering,et al.  Stressing the role of FoxO proteins in lifespan and disease , 2007, Nature Reviews Molecular Cell Biology.

[27]  I. Fidler,et al.  Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. , 2007, Endocrine reviews.

[28]  B. Gogebakan,et al.  CDC25A gene 263C/T, -350C/T, and -51C/G polymorphisms in breast carcinoma , 2010, Tumor Biology.

[29]  Larry Norton,et al.  Tumor Self-Seeding by Circulating Cancer Cells , 2009, Cell.

[30]  Jean-Marc Guinebretière,et al.  A six-gene signature predicting breast cancer lung metastasis. , 2008, Cancer research.

[31]  M. Loda,et al.  Role of the Cdc25A phosphatase in human breast cancer. , 2000, The Journal of clinical investigation.

[32]  Christian R. Dolder,et al.  A review of lapatinib ditosylate in the treatment of refractory or advanced breast cancer , 2007, Therapeutics and clinical risk management.

[33]  Q. Cai,et al.  Aberrant Polo-Like Kinase 1-Cdc25A Pathway in Metastatic Hepatocellular Carcinoma , 2008, Clinical Cancer Research.

[34]  H Nojima,et al.  Cdc25A is a novel phosphatase functioning early in the cell cycle. , 1994, The EMBO journal.

[35]  G. Hortobagyi,et al.  Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  D. Nimbalkar,et al.  Transforming growth factor beta facilitates beta-TrCP-mediated degradation of Cdc25A in a Smad3-dependent manner. , 2005, Molecular and cellular biology.

[37]  E. El-Omar,et al.  The matrix metalloproteinase/tissue inhibitor of matrix metalloproteinase profile in colorectal polyp cancers , 2009, Histopathology.

[38]  A. Agarwal,et al.  Blockade of PAR1 signaling with cell-penetrating pepducins inhibits Akt survival pathways in breast cancer cells and suppresses tumor survival and metastasis. , 2009, Cancer research.

[39]  R. Flavell,et al.  An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance. , 2009, Immunity.

[40]  V. Trivedi,et al.  Platelet Matrix Metalloprotease-1 Mediates Thrombogenesis by Activating PAR1 at a Cryptic Ligand Site , 2009, Cell.

[41]  A. Gudkov,et al.  Cdk4 disruption renders primary mouse cells resistant to oncogenic transformation, leading to Arf/p53-independent senescence. , 2002, Genes & development.

[42]  J. Massagué,et al.  Molecular basis of metastasis. , 2008, The New England journal of medicine.

[43]  L. Mao,et al.  Overexpression of cdc25A and cdc25B is frequent in primary non-small cell lung cancer but is not associated with overexpression of c-myc. , 1998, Cancer research.

[44]  K. Arden.  FoxOs in Tumor Suppression and Stem Cell Maintenance , 2007, Cell.

[45]  J. Rudolph.  Inhibiting transient protein–protein interactions: lessons from the Cdc25 protein tyrosine phosphatases , 2007, Nature Reviews Cancer.

[46]  Michele Pagano,et al.  Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damage , 2003, Nature.

[47]  Hui Zhao,et al.  Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[48]  H. Piwnica-Worms,et al.  Chk1 Kinase Negatively Regulates Mitotic Function of Cdc25A Phosphatase through 14-3-3 Binding , 2003, Molecular and Cellular Biology.

[49]  John Quackenbush,et al.  Confounding effects in "A six-gene signature predicting breast cancer lung metastasis". , 2009, Cancer research.

[50]  S. Barsky,et al.  A Novel Mechanism of Indole-3-Carbinol Effects on Breast Carcinogenesis Involves Induction of Cdc25A Degradation , 2010, Cancer Prevention Research.

[51]  D. Tindall,et al.  CDK2-Dependent Phosphorylation of FOXO1 as an Apoptotic Response to DNA Damage , 2006, Science.

[52]  M. J. Abedin,et al.  Autophagy delays apoptotic death in breast cancer cells following DNA damage , 2007, Cell Death and Differentiation.

[53]  D. Nimbalkar,et al.  Hemizygous disruption of Cdc25A inhibits cellular transformation and mammary tumorigenesis in mice. , 2007, Cancer research.

[54]  D. Kennedy,et al.  A Comparative Review of Thermography as a Breast Cancer Screening Technique , 2009, Integrative cancer therapies.

[55]  Zhiyong Guo,et al.  Available Online , 1600 .

[56]  J. Cleveland,et al.  Essential Role of Phospholipase Cγ2 in Early B-Cell Development and Myc-Mediated Lymphomagenesis , 2006, Molecular and Cellular Biology.

[57]  E. Appella,et al.  GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancers. , 2008, Cancer cell.

[58]  R. Maestro,et al.  Overexpression of CDC25A and CDC25B in head and neck cancers. , 1997, Cancer research.

[59]  D. Christiani,et al.  Matrix metalloproteinase 1, 3 and 12 polymorphisms and esophageal adenocarcinoma risk and prognosis. , 2009, Carcinogenesis.

[60]  I. Hoffmann,et al.  Cell cycle regulation by the Cdc25 phosphatase family. , 2000, Progress in cell cycle research.

[61]  Bernard Ducommun,et al.  CDC25 phosphatases in cancer cells: key players? Good targets? , 2007, Nature Reviews Cancer.

[62]  I. Hoffmann,et al.  Ectopic Expression of Cdc25A Accelerates the G1/S Transition and Leads to Premature Activation of Cyclin E- and Cyclin A-Dependent Kinases , 1999, Molecular and Cellular Biology.