Heterogeneous intracellular TRAIL-receptor distribution predicts poor outcome in breast cancer patients

Upon ligand binding, plasma membrane located TNF-related apoptosis-inducing ligand (TRAIL)-receptors 1 and 2 induce apoptosis as well as cancer-promoting signaling in cancer cells. TRAIL-R3 and TRAIL-R4 are believed to negatively regulate TRAIL-mediated apoptosis. Intracellular localization of TRAIL-receptors, as observed in many tumor cells, has been associated with oncogenic features, which are distinct from membrane-associated TRAIL-R signaling. Here, analyzing a panel of 354 breast cancer specimens, we found that an unfavorable outcome correlating with cancer-promoting properties of TRAIL-R1, -R2, and -R4 was most significantly defined by their intracellular distribution and mutual co-expression. A nuclear or cytoplasmic heterogeneous expression pattern correlated with markedly decreased overall survival, while a homogeneous distribution of expression, i.e. nuclear and cytoplasmic expression, was associated with favorable breast cancer surrogate markers corresponding with an excellent survival prognosis (Hazard ratio: 0.098; p < 0.001). No association with specific intrinsic breast cancer subtypes was found. As intracellular TRAIL-R homo- compared to heterogeneity demonstrated superior prognostic values to single receptor analyses and conventional breast cancer surrogate markers, establishing a combined expression score of intracellular expression patterns of TRAIL-R1, -R2, and -R4 may provide a new, more robust method for risk stratification in breast cancer patients.