Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) loss in canine mammary carcinoma

Escaping apoptosis is a hallmark of cancer. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), a central molecule that regulates the extrinsic apoptotic pathway, has been widely investigated in human oncology; however, investigations focusing on the endogenous expression of TRAIL in canine tumours are lacking. Therefore, we aimed to examine the expression of endogenous TRAIL in canine mammary tumours and analysed its correlation with downstream molecules Fas-associated protein with death domain (FADD) and caspase-3, and to the apoptotic index. A total of 147 samples, classified as normal mammary gland (n = 9), mammary adenoma (n = 30), low-grade carcinoma (n = 42) and high-grade carcinoma (n = 66), were included in the immunohistochemical analyses, and 43 samples with sufficient levels of RNA were analysed via RNA in situ hybridization and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. In immunohistochemistry, TRAIL protein expression was significantly decreased in high-grade carcinoma compared to those in normal mammary gland and adenoma, with similar downregulation of TRAIL mRNA expression. Also, FADD and caspase-3 expression positively correlated with TRAIL expression. However, the apoptotic index was paradoxically elevated in high-grade tumours. Overall, these results suggest that the loss of TRAIL accompanied by dysregulation of TRAIL-induced extrinsic apoptotic pathway molecules could affect malignant progression of canine mammary tumours.