Data from X-Linked Ectodermal Dysplasia Receptor Is Downregulated in Breast Cancer via Promoter Methylation

Purpose: The X-linked ectodermal dysplasia receptor (XEDAR) is a novel receptor of the tumor necrosis factor receptor family that binds to ectodysplasin-A2 (EDA-A2) and induces cell death. The purpose of this study was to determine the tumor-suppressive potential of XEDAR in the development of breast cancer.Experimental Design: We analyzed the expression of XEDAR in breast cancer cell lines and tumor samples using quantitative real-time PCR analysis and immunoblotting. We analyzed the human XEDAR gene promoter for the presence of any CpG island and examined its methylation status using methylation-specific real-time PCR. We examined the effect of 5-aza-2′-deoxycytidine on the expression of XEDAR and sensitivity to EDA-A2–induced apoptosis in breast cancer cell lines.Results: Expression of XEDAR, but not EDA-A2, was downregulated in most tumorigenic breast cancer cell lines and tumor samples. Loss of XEDAR expression correlated with the hypermethylation of its promoter. Ectopic expression of XEDAR in MDA-MB-231 cells resulted in significant induction of apoptosis and reduction in colony formation. Treatment with 5-aza-2′-deoxycytidine restored XEDAR expression in breast cancer cell lines with methylated XEDAR promoter and sensitized them to EDA-A2–induced cell death.Conclusions: Our results suggest that XEDAR expression is downregulated in most breast cancers via promoter methylation, which may contribute to accelerated tumor development by blocking EDA-A2–induced cell death. XEDAR may represent a novel breast tumor suppressor gene, and restoration of its expression by treatment with DNA demethylating agents may represent an attractive approach for the treatment of breast cancer. Clin Cancer Res; 16(4); 1140–8