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Vol. 19, Issue 9, 3745-3757, September 2008

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

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

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

Submitted February 15, 2008; Revised May 19, 2008; Accepted June 16, 2008
Monitoring Editor: Carl-Henrik Heldin

Prostate derived ETS factor (PDEF) is an ETS (epithelial-specific E26 transforming sequence) 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 >200 human genes that displayed a common differential expression pattern in three invasive breast cancer cell lines after 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, chromatin immunoprecipitation studies identified PDEF as a direct negative regulator of the metastasis-associated gene uPA and phenotypic rescue experiments demonstrate that exogenous urokinase plasminogen activator (uPA) expression can restore the migratory ability of invasive breast cancer cells expressing PDEF. Furthermore, immunofluorescence studies identify the subcellular relocalization of urokinase plasminogen activator receptor (uPAR), LIM and SH3 protein (LASP1), and vasodilator-stimulated protein (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)

Abbreviations used: ChIP, chromatin immunoprecipitation; EBS, ETS binding site; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; ETS, E26 transforming sequence; ITGA5(6), integrin 5(6); LASP1, Lim and SH3 protein; PDEF, prostate-derived epithelial factor; pFAK, phosphorylated focal adhesion kinase; uPA, urokinase plasminogen activator (PLAU); uPAR, urokinase plasminogen activator receptor (PLAUR); VASP, vasodilator-stimulated phosphoprotein.

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