TRAIL Death Receptor–4 Expression Positively Correlates With the Tumor Grade in Breast Cancer Patients With Invasive Ductal Carcinoma

Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level

“…10 In solid tumors, analysis of TRAIL receptor expression was often performed by immunohistochemistry, and although this method does not provide the information whether the receptors are expressed at the cell surface, these studies indicate that the extent of expression of the antagonistic receptors TRAIL-R3 and TRAIL-R4 is probably underestimated. 9,[19][20][21] Engagement of apoptosis upon TRAIL stimulation in a given tissue type, primary tumor or cell line, relies on the contribution of multiple players, including proapoptotic and prosurvival factors, which ultimately determine cell fate. It has recently been demonstrated that naturally occurring differences in the levels or states of proteins regulating TRAIL signaling are the primary causes of cell-to-cell variability.…”

“…6,7 TRAIL-induced cell death can be specifically inhibited by two membrane-bound antagonistic receptors, TRAIL-R3 (DcR1, LIT or TRID) or TRAIL-R4 (DcR2 or TRUNDD). 2 These receptors have been shown to be expressed and to prevent TRAIL-induced cell death in various human primary tumor cells, including lymphomas, lung, breast and prostate carcinomas, [8][9][10] but the inhibitory potential of this receptor still remains controversial. 11 Although TRAIL-R3 is a GPI-anchored receptor that sequesters TRAIL into lipid rafts, TRAIL-R4 interacts with TRAIL-R2 within the DISC, and impairs caspase-8 processing, 12 thus, inhibiting TRAILinduced apoptosis.…”

Is TRAIL the holy grail of cancer therapy?

“…As a result it may be that some tumours have even exploited TRAIL signalling for their own advantage. In line with this, TRAIL-R1 expression has been shown to positively correlate with tumour grade in patients with breast cancer [80], although it can not be excluded that high TRAIL-R1 expression is an effect of higher grade tumours, rather than a cause. Caveats for the use of TRAIL therapy in later stages of cancer also arise since migrating gliomas activate their PI3K pathways and become less sensitive to TRAIL-induced apoptosis [78].…”

Mislocalization of death receptors correlates with cellular resistance to their cognate ligands in human breast cancer cells

“…The IHC score was determined by combining the intensity and distribution scores (percentage of the positivity in the tumor tissues) scores (37). The staining intensity was based on a 4-point system: 0 (no staining), 1 (weak), 2 (moderate), and 3 (strong).…”