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

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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.

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Acknowledgments

The antibodies for TRAIL-R1, TRAIL-R2, and TRAIL-R4 were kindly provided by Henning Walczak, UCL Cancer Institute, London.

Funding

This work was supported by the Deutsche Forschungsgemeinschaft (TR 1063/3-1 given to AT) and the German Cancer Aid (Max Eder Junior Research Group funding awarded to SvK).

Author information

Author notes

  1. Christian Schem and Anna Trauzold share co-senior authorship.

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany

    Thorsten Heilmann, Ibrahim Alkatout, Antonia Wenners, Nicolai Maass & Christian Schem

  2. Department of Pathology, General Pathology and Hematopathology, University Hospital Schleswig-Holstein, Kiel, Germany

    Florian Vondung, Sandra Krüger, Wolfram Klapper & Christoph Röcken

  3. Institute of Medical Informatics and Statistics, Christian-Albrechts-University of Kiel, Kiel, Germany

    Christoph Borzikowsky & Silke Szymczak

  4. Fertility Center Kiel, Kiel, Germany

    Antonia Wenners

  5. Frauenpraxis Ostufer, Kiel, Germany

    Maret Bauer

  6. Department of Translational Genomics, University Hospital Cologne, Cologne, Germany

    Silvia von Karstedt

  7. Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

    Silvia von Karstedt

  8. Mammazentrum am Krankenhaus Jerusalem, Hamburg, Germany

    Christian Schem

  9. Institute for Experimental Cancer Research, Christian-Albrechts-University of Kiel, Arnold-Heller Str. 3 (Haus 17), 24105, Kiel, Germany

    Anna Trauzold

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  1. Thorsten Heilmann
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Contributions

TH, CS, and AT designed the study, analyzed the data, and wrote the manuscript. FV, SK, and CR performed the tissue staining and histological examination and established the TRAIL-receptor scoring system. CB and SS conducted statistical computations and preparation of the figures. IA, AW, MB, and WK established the breast cancer patients’ tissue microarray and participated in the design of the study. NM and SvK participated in the conception and writing of the manuscript and data analyses.

All authors read and approved the manuscript.

Corresponding author

Correspondence to Anna Trauzold.

Ethics declarations

This study was conducted with the approval of the local ethics committee (Faculty of Medicine, Christian-Albrechts-University Kiel, Germany; #D450/10).

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The authors declare that they have no conflict of interest.

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Thorsten Heilmann and Florian Vondung share co-first authorship.

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Heilmann, T., Vondung, F., Borzikowsky, C. et al. Heterogeneous intracellular TRAIL-receptor distribution predicts poor outcome in breast cancer patients. J Mol Med 97, 1155–1167 (2019). https://doi.org/10.1007/s00109-019-01805-w

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