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

Thorsten Heilmann, Florian Vondung, Christoph Borzikowsky, Silke Szymczak, Sandra Krüger, Ibrahim Alkatout, Antonia Wenners, Maret Bauer, Wolfram Klapper, Christoph Röcken, Nicolai Maass, Silvia von Karstedt, Christian Schem, Anna Trauzold*

*Corresponding author for this work
2 Citations (Scopus)


Abstract: 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.

Original languageEnglish
JournalJournal of Molecular Medicine
Issue number8
Pages (from-to)1155-1167
Number of pages13
Publication statusPublished - 01.08.2019


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