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, trail-r2, and trail-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 and discriminated high-risk breast cancer patients from low-risk patients with a homogeneous distribution of expression, i.e., nuclear and cytoplasmic expression. the homogeneous trail-r expression was associated with favorable breast cancer surrogate markers corresponding with excellent survival prognoses at 5 years after diagnosis (hazard ratio, 0.043) and over the complete course of follow-up (hazard ratio, 0.098; both p < 0.001). no associations with specific intrinsic breast cancer subtypes were found. our data suggest that the determination of intracellular co-expression patterns of trail-r1, trail-r2, and trail-r4 provides an innovative and robust method for risk stratification in breast cancer patients beyond conventional prognostic markers.