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

• DOI: 10.1007/s00109-019-01805-w
• Publication Date: 2019-06-10T04:02:38Z
• Authors: Thorsten Heilmann; Florian Vondung; Christoph Borziko...; Silke Szymczak; Sandra Krüger; Ibrahim Alkatout; Antonia Wenners; Maret Bauer; Wolfram Klapper; Christoph Röcken; Nicolai Maass; Silvia von Karstedt; Christian Schem; Anna Trauzold
• Keywords: Breast Neoplasms; Middle Aged; Disease-Free Survival; Neoplasm Proteins; 3. Good health; Gene Expression Regulation, Neoplastic; Survival Rate; MicroRNAs; Receptors, TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor Decoy Receptors; Biomarkers, Tumor; Humans; Female; RNA, Neoplasm; Aged; Retrospective Studies

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. KEY MESSAGES: A total of 70% of breast cancer specimens show comparably high levels of intracellular TRAIL-Rs. Nuclear or cytoplasmic TRAIL-R co-expression occurs in the majority of tumors. A total of 25% of tumors show a heterogeneous expression of cytoplasmic or nuclear TRAIL-Rs. Patients with a heterogeneous TRAIL-R expression present with poor prognoses. Additive TRAIL-R-based risk stratification comprises different breast cancer subtypes.