Abstract
Ectodysplasin A receptor (EDAR) is a death receptor in the Tumour Necrosis Factor Receptor (TNFR) superfamily with roles in the development of hair follicles, teeth and cutaneous glands. Here we report that human Oestrogen Receptor (ER) negative breast carcinomas which display squamous differentiation express EDAR strongly. Using a mouse model with a high Edar copy number, we show that elevated EDAR signalling results in a high incidence of mammary tumours in breeding female mice. These tumours resemble the EDAR-high human tumours in that they are characterised by a lack of oestrogen receptor expression, contain extensive squamous metaplasia, and display strong β-catenin transcriptional activity. In the mouse model, all of the tumours carry somatic deletions of the third exon of the CTNNB1 gene that encodes β-catenin. Deletion of this exon yields unconstrained β-catenin signalling activity. We also demonstrate that β-catenin activity is required for transformed cell growth, showing that increased EDAR signalling creates an environment in which β-catenin activity can readily promote tumourigenesis. Together, this work identifies a novel death receptor oncogene in breast cancer, whose mechanism of transformation is based on the interaction between the WNT and Ectodysplasin A (EDA) pathways.
Highlights
Ectodysplasin A receptor (EDAR) is one of eight death domain receptors encoded within the human genome [1]
EDAR is highly expressed in basal and metaplastic human breast cancers The action of EDAR in breast tissue, its similarity to the known mammary oncogene RANK, and its ability to activate NFκB, led us to investigate whether EDAR could be a causative factor in human breast cancer
As the area of epithelial tissue remaining in wild-type and Edartg951/951 mice was had undergone squamous metaplasia, and an activation of the WNT/β-catenin signalling pathway (expression of WNT10B and not different at involution day 6 (Fig. S6D, E), we conclude that the LEF1)
Summary
Ectodysplasin A receptor (EDAR) is one of eight death domain receptors encoded within the human genome [1]. EDAR signalling is stimulated by its ligand, Ectodysplasin A (EDA), leading to signal transduction through EDAR-associated death domain to the canonical NFκB pathway. Loss-of function mutations within EDAR pathway components lead to Hypohydrotic Ectodermal Dysplasia (HED), which is characterised by missing or misshapen teeth, sparse hair, a reduced ability to sweat [3, 4] and lack of full mammary development [5, 6]. Similar phenotypes are seen in the mouse strains, downless (EdardlJ) and Tabby (EdaTa/Ta), which carry loss-offunction mutations in the receptor and ligand respectively [4, 7, 8], and when NFκB signalling is reduced in the developing skin [9]. The developmental action of EDAR is tightly associated with WNT/ β-catenin signalling, with several levels of interaction between these pathways having been described in early hair follicle development [10, 11]
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