TRAIL-R2 in the shadows: Epigenetic silencing and clinical implications in breast cancer

Copyright: © 2026 Khursheed et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Breast cancer is considered to be one of the most widespread malignancies, however, its molecular processes are not fully comprehended. Another important epigenetic process that regulates the expression of genes in cancer is promoter methylation. TRAIL-R2 is also a key mediator of apoptosis but its clinical implications and epigenetic regulation in breast cancer are not clearly understood. In this research, the level of the promoter of the gene TRAIL-R2 in the matched tumor and normal breast tissues was analyzed using methylation-specific PCR and the level of the mRNA and protein products in the matched tumor and normal breast tissues were measured using quantitative real-time PCR and western blotting. Methylation of TRAIL-R2 promoter was significantly enhanced in tumor tissues and was negatively correlated with the levels of mRNA and protein. We found that hypermethylation was much more common in invasive ductal carcinoma patients and in patients with a history of use of oral contraceptives. A decreased expression of mRNA of TRAIL-R2 was significantly related to advanced TNM stage (III–IV) and the absence of progesterone receptor, and low protein expression was significantly related to postmenopausal status. These results suggest that aggressive clinicopathological phenotypes are associated with TRAIL-R2 silencing via promoter hypermethylation that may be relevant as a prognostic biomarker and therapeutic target in breast cancer.