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MBC in Press, published online ahead of print June 25, 2008
Mol. Biol. Cell 10.1091/mbc.E08-02-0154

A more recent version of this article appeared on September 1, 2008
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Submitted on February 15, 2008
Revised on May 19, 2008
Accepted on June 16, 2008

Global Gene Expression Analysis Identifies PDEF Transcriptional Networks Regulating Cell Migration during Cancer Progression

David P. Turner,* Victoria J. Findlay,* A. Darby Kirven,{dagger} Omar Moussa,* and Dennis K. Watson*

*Department of Pathology and Laboratory Medicine, Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425; {dagger}South Carolina Governor’s School for Science and Mathematics, Hartsville, SC 29550

Monitoring Editor: Carl-Henrik Heldin

PDEF is an epithelial specific ETS family member that has been identified as a potential tumor suppressor. In multiple invasive breast cancer cells, PDEF expression inhibits cell migration by preventing the acquisition of directional morphological polarity conferred by changes in cytoskeleton organization. In this study, microarray analysis was used to identify over 200 human genes that displayed a common differential expression pattern in three invasive breast cancer cell lines following expression of exogenous PDEF protein. Gene ontology associations and data mining analysis identified focal adhesion, adherens junctions, cell adhesion and actin cytoskeleton regulation as cell migration associated interaction pathways significantly impacted by PDEF expression. Validation experiments confirmed the differential expression of four cytoskeleton-associated genes with known functional associations with these pathways: uPA, uPAR, LASP1 and VASP. Significantly, ChIP studies identified PDEF as a direct negative regulator of the metastasis associated gene uPA and phenotypic rescue experiments demonstrate that exogenous uPA expression can restore the migratory ability of invasive breast cancer cells expressing PDEF. Furthermore, immunofluorescence studies identify the subcellular relocalization of uPAR, LASP1 and VASP as a possible mechanism accounting for the loss of morphological polarity observed upon PDEF expression.

Address correspondence to: Dennis K. Watson (Watsondk{at}musc.edu)




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[Abstract] [Full Text] [PDF]


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