DNA methylation-mediated regulation of TRAIL pathway components (DR5, DcR2, and CASP3) in breast cancer: molecular mechanisms and therapeutic implications.

Authors

Nuzhat Khursheed, Suhail Ashraf, Qurat-Ul-Quadir, Allah-U-Deen Khursheed, Asia Asiaf, Showkat Ahmad Ganie

Published in

Molecular biology reports. Volume 53. Issue 1. Oct 10, 2026. Epub Oct 10, 2026.

Abstract

Breast cancer is the most common cancer and a leading cause of cancer-related mortality among women worldwide. Survival by apoptosis is a mechanism that is key to disease activity and failure to response to therapy. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway has been identified as a therapeutic target as it is capable of selectively inducing apoptosis in cancer cells via death receptors, notably TRAIL receptor-2 (DR5/TNFRSF10B), with subsequent activation of downstream caspases, such as caspase-3. But breast cancer cells can escape TRAIL induced apoptosis by modulating or down-regulating expression of death-receptors, up-regulating expression of decoy-receptors (e.g., DcR2/TNFRSF10D), and regulating the downstream apoptotic regulators. New studies reveal that epigenetic changes, such as DNA methylation, affect genes associated with apoptosis and could be responsible for resistance to TRAIL. This review critically evaluates the latest evidence on epigenetic regulation of important factors of the TRAIL pathway, including DR5 and also DcR2 and caspase-3. The effects of promoter DNA methylation on gene expression, apoptotic signaling, TRAIL resistance and its potential as a clinical prognostic/predictive biomarker are discussed. Data suggest that hypermethylation of the DR5 promoter may lead to the silencing of DR5 and the failure to promote apoptosis through TRAIL, while aberrant methylation of DcR2 may affect apoptotic signals. CASP3 methylation, in turn, can diminish the apoptotic function and cause therapeutic resistance. Taken together, these results identify DNA methylation as a key modulator of TRAIL-mediated killing and provide clues for the identification of potential biomarkers and epigenetic therapeutic approaches to regain apoptotic functions in breast cancer.

PMID:
42859250
Bibliographic data and abstract were imported from PubMed on 11 Oct 2026.

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