Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized 
by late diagnosis and treatment resistance. Recurrent genetic alterations in 
defined genes in association with perturbations of developmental cell signaling 
pathways have been associated with PDAC development and progression. Here, we 
show that GATA6 contributes to pancreatic carcinogenesis during the temporal 
progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway 
activation. GATA6 is recurrently amplified by both quantitative-PCR and 
fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia 
and in PDAC tissues, and GATA6 copy number is significantly correlated with 
overall patient survival. Forced overexpression of GATA6 in cancer cell lines 
enhanced cell proliferation and colony formation in soft agar in vitro and 
growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated 
knockdown of GATA6 led to corresponding decreases in these same parameters. The 
effects of GATA6 were found to be due to its ability to bind DNA, as forced 
overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in 
vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. 
A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a 
dysregulated gene in association with GATA6 knockdown, and direct binding of 
GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and 
electrophoretic mobility shift assays. Transient transfection of GATA6, but not 
mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and 
secretion of DKK1 protein into culture media. Forced overexpression of DKK1 
antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. 
These findings illustrate that one mechanism by which GATA6 promotes pancreatic 
carcinogenesis is by virtue of its activation of canonical Wnt signaling via 
regulation of DKK1.