Abstract 1425: Significance of Dickkopf-3 overexpression in the pathogenesis of esophageal adenocarcinoma

Abstract Ninety percent of those diagnosed with esophageal adenocarcinoma ultimately die of their disease highlighting the need for novel therapeutic targets. In order to identify significant molecular changes and potential pathways involved in the progression to esophageal adenocarcinoma, 46 esophagectomy samples, including Barrett's metaplasia, low- and high-grade dysplasia, and esophageal adenocarcinoma, were evaluated using oligonucleotide microarrays. Dickkopf-3 (Dkk-3), a divergent member of the Wnt inhibitor family, was overexpressed in 33.3% (5 of 15) of esophageal adenocarcinoma samples relative to Barrett's metaplasia. The goal of this study was to define the functional significance of Dkk-3 overexpression in esophageal adenocarcinoma. Dkk-3 protein was present at moderate to high levels in 46.8% (29 of 62) of esophageal adenocarcinoma on a tissue microarray. Stable transfection of Dkk-3 into the esophageal adenocarcinoma cell line OE33 lead to significantly increased proliferation 1.6 times vector controls (p < .005). In addition, OE33 cells stably transfected with Dkk-3 showed significantly greater invasion on matrigel assay than native OE33 cells (p < .005). There was no significant decrease in Wnt pathway activation by TOPFLASH assay after transfection of Dkk-3 when compared to OE33 native and vector controls suggesting that overexpression of Dkk-3 acts through a Wnt-independent pathway in esophageal adenocarcinoma. Levels of SMAD4, a key downstream mediator of the TGF-ß pathway, were increased on Western blot after treatment with activin, a member of the TGF-ß superfamily, in OE33 cells stably transfected with Dkk-3 when compared to native and vector controls. These findings suggest that Dkk-3 may be important in mediating proliferation and invasion of esophageal adenocarcinoma through the TGF-β pathway and that Dkk-3 could be a novel therapeutic target in the treatment or prevention of metastatic disease in a cancer with otherwise limited therapeutic options. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1425. doi:10.1158/1538-7445.AM2011-1425