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

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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 <i>XEDAR</i> 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 <i>XEDAR</i> and sensitivity to EDA-A2–induced apoptosis in breast cancer cell lines.</p><p><b>Results:</b> Expression of <i>XEDAR</i>, but not <i>EDA-A2</i>, was downregulated in most tumorigenic breast cancer cell lines and tumor samples. Loss of <i>XEDAR</i> 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 <i>XEDAR</i> expression in breast cancer cell lines with methylated <i>XEDAR</i> promoter and sensitized them to EDA-A2–induced cell death.</p><p><b>Conclusions:</b> Our results suggest that <i>XEDAR</i> expression is downregulated in most breast cancers via promoter methylation, which may contribute to accelerated tumor development by blocking EDA-A2–induced cell death. <i>XEDAR</i> 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</p></div>