ErbB3 Binding Protein 1 Represses Metastasis-Promoting Gene Anterior Gradient Protein 2 in Prostate Cancer

Abstract

Dysregulation of the developmental gene anterior gradient protein 2 (AGR2) has been associated with a metastatic phenotype, but its mechanism of action and control in prostate cancers is unknown. In this study, we show that overexpression of AGR2 promotes the motility and invasiveness of nonmetastatic LNCaP tumor cells, whereas silencing of AGR2 in the metastatic derivative C4-2B blocks invasive behavior. ErbB3 binding protein 1 (EBP1), a putative repressor of AGR2, is attenuated in prostate cancer. We show that the anti-invasive effect of EBP1 occurs, at least in part, through its ability to inhibit AGR2 expression. Mechanistic investigations indicate that EBP1 downregulates Foxa1- and Foxa2-stimulated AGR2 transcription and decreases metastatic behavior. In contrast, EBP1 ablation upregulates AGR2 via Foxa1- and Foxa2-stimulated AGR2 promoter activity and increases metastatic behavior. In both prostate cell lines and primary tumors, we documented an inverse correlation between EBP1 and AGR2 levels. Collectively, our results reveal an EBP1-Foxa-AGR2 signaling circuit with functional significance in metastatic prostate cancer.