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A Name Like No Other

March 19, 2010

XEDAR induces cell deathIn biomedical research, names sometimes can be deceiving at first. Take a transmembrane protein receptor that is highly expressed in epidermal tissues of a developing fetus. The receptor is known as X-Linked Ectodermal Dysplasia Receptor, or XEDAR, because it exclusively binds a protein encoded by the ectodysplasin (Eda) gene. The assumption being, because mutations in Eda are linked to the X-linked form of a human developmental disorder called hypohidrotic ectodermal dysplasia (HED), an altered XEDAR receptor also probably plays some role in the condition.

But follow-up work has yet to identify anyone who has HED and mutations in the XEDAR gene. Instead, laboratory research has revealed a structurally fascinating protein that belongs to the much-studied tumor necrosis factor (TNF) family of receptors. Interestingly, XEDAR lacks a structural motif that is common to TNF members called a death domain, a no-go molecular zone that initiates programmed cell death, or apoptosis. And yet, XEDAR can initiate apoptosis through an alternate cellular route. This conserved apoptotic function led some to wonder whether XEDAR, like its sibling death-domain TNF receptors, also acts as a tumor suppressor protein that some cell types inactivate as they turn cancerous.

That’s when a team of NIDCR grantees and colleagues brought XEDAR and its presumed biological connection to HED full circle. People born with HED lack or partially develop several tissues and organs derived from the ectoderm, one of the early fetal germ layers. These typically include teeth, hair, and sweat glands. This is noteworthy because many researchers consider the developmental origins of the breast to be as a sweat gland, and women with HED sometimes lack or have underdeveloped breasts. Could XEDAR act as a tumor suppressor in a developing breast, a tissue formed in part through the proliferation of epithelial cells of ectodermal origin? If so, XEDAR might be one of the tumor suppressors that breast cancer cells later sequentially target to enable their dysregulated growth.

In the February 15 issue of the journal Clinical Cancer Research, the scientists report that their hunch was correct. They found that XEDAR was silenced in most of a large panel of breast cancer cell lines and tumor samples. The silencing resulted from hypermethylation of the XEDAR gene. Hypermethylation occurs when a methyl group attaches to a gene. The methyl tag alters the gene’s ability to interact with needed transcription regulators, thereby turning off the gene. When the scientists added XEDAR to the cell lines, they detected a significant increase in apoptosis and reduced colony formation. These researchers concluded that their results “may have considerable implications for the diagnosis and treatment of breast cancer,” but additional studies will be needed to pursue this lead.


  • X-Linked Ectodermal Dysplasia Receptor Is Downregulated in Breast Cancer via Promoter Methylation.  Vasu Punj , Hittu Matta , and Preet M. Chaudhary.  Clin Cancer Res 2010 Feb 15;16(4):1140-8. 

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This page last updated: February 26, 2014