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Sef Regulates Epithelial‐Mesenchymal Transition in Breast Cancer Cells

Sef (similar expression to fgf), also know as IL17RD, is a transmembrane protein shown to inhibit fibroblast growth factor signaling in developmental and cancer contexts; however, its role as a tumor suppressor remains to be fully elucidated. Here, we show that Sef regulates epithelial‐mesenchymal transition (EMT) in breast cancer cell lines. Sef expression was highest in the normal breast epithelial cell line MCF10A, intermediate expression in MCF‐7 cells and lowest in MDA‐MB‐231 cells. Knockdown of Sef increased the expression of genes associated with EMT, and promoted cell migration, invasion, and a fibroblastic morphology of MCF‐7 cells. Overexpression of Sef inhibited the expression of EMT marker genes and inhibited cell migration and invasion in MCF‐7 cells. Induction of EMT in MCF10A cells by TGF‐β and TNF‐α resulted in downregulation of Sef expression concomitant with upregulation of EMT gene expression and loss of epithelial morphology. Overexpression of Sef in MCF10A cells partially blocked cytokine‐induced EMT. Sef was shown to block β‐catenin mediated luciferase reporter activity and to cause a decrease in the nuclear localization of active β‐catenin. Furthermore, Sef was shown to co‐immunoprecipitate with β‐catenin. In a mouse orthotopic xenograft model, Sef overexpression in MDA‐MB‐231 cells slowed tumor growth and reduced expression of EMT marker genes. Together, these data indicate that Sef plays a role in the negative regulation of EMT in a β‐catenin dependent manner and that reduced expression of Sef in breast tumor cells may be permissive for EMT and the acquisition of a more metastatic phenotype. J. Cell. Biochem. 117: 2346–2356, 2016. © 2016 Wiley Periodicals, Inc.