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Papers In Press, published online ahead of print August 26, 2002
Medicine Dept., Calcium Research Laboratory, McGill University Health Centre, Montreal, QC H3A 1A1
Corresponding Author: shafaat.rabbani{at}staff.mcgill.ca
Urokinase-Type Plasminogen Activator is a member of the serine protease family, and can break down various components of the extracellular matrix to promote growth, invasion, and metastasis of several malignancies including breast cancer. In the current study we examined the role that the DNA methylation machinery might be playing in regulating differential uPA gene expression in breast cancer cell lines. uPA mRNA is expressed in the highly invasive, hormone insensitive human breast cancer cell line MDA-MB-231, but not in hormone responsive cell line MCF-7. Using methylation sensitive PCR, we show that 90% of CpG dinucleotides in the uPA promoter are methylated in MCF-7 cells, whereas fully demethylated CpGs were detected in MDA-MB-231 cells. uPA promoter activity, which is directly regulated by the Ets-1 transcription factor, is inhibited by methylation as determined by uPA promoter-luciferase reporter assays. We then tested whether the state of expression and methylation of the uPA promoter correlates with the global level of DNA methyltransferase and demethylase activities in these cell lines. We show that maintenance DNA methyltransferase activity is significantly higher in MCF-7 cells than in MDA-MB-231 cells, whereas demethylase activity is higher in MDA-MB-231 cells. We suggest that the combination of increased DNA methyltransferase activity with reduced demethylase activity contributes to the methylation and silencing of uPA expression in MCF-7 cells. The converse is true in MDA-MB-231 cells, which represents a late stage highly invasive breast cancer. The histone deacetylase inhibitor, Trichostatin A induces the expression of the uPA gene in MDA-MB-231 cells but not in MCF-7 cells. This supports the hypothesis that DNA methylation is the dominant mechanism involved in the silencing of uPA gene expression. Taken together, these results provide insight into the mechanism regulating the transcription of the uPA gene in the complex multi-step process of breast cancer progression.
J. Biol. Chem, 10.1074/jbc.M201864200
Submitted on February 25, 2002
Revised on August 26, 2002
Accepted on August 26, 2002
Regulation of DNA methylation in human breast cancer: Effect on the urokinase-type plasminogen activator gene production and tumor invasion
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