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Derlin-1 (Derl-1) is a transporter protein for the export of misfolded proteins from the endoplasmic reticulum (ER) and an inhibitor of ER stress-induced apoptosis. There is greater expression of Derl-1 mRNA in laser microdissected lymph node metastases of mammary adenocarcinomas than in non-neoplastic mammary gland tissue from the same dog. The aim of the present study was to immunohistochemically assess Derl-1 protein expression in neoplastic and non-neoplastic canine mammary tissues. Samples of primary mammary adenocarcinomas were collected from 54 dogs in addition to the nodal metastases of these tumours and intralymphatic neoplastic cells. Non-neoplastic mammary gland tissue was taken from the same animals. Samples of mammary adenomas were collected from a further 44 dogs in addition to non-neoplastic mammary gland from the same animals. There were significant (P < or = 0.05) differences in Derl-1 expression between the different mammary tissues. Weak Derl-1 expression was found in non-neoplastic gland and mammary adenomas, moderate expression in adenocarcinomas, moderate to marked expression in lymph node metastases and marked expression in intralymphatic tumour cells. Neoplastic mammary gland cells therefore appear to have an increased stress-associated unfolded protein response, and this is highest in intralymphatic tumour cells. Weak Derl-1 protein expression was also found in vascular endothelial cells and fibrocytes and occasionally in lymphatic lining cells.