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The TRAIL system is over-expressed in breast cancer and FLIP a marker of good prognosis

  • Original Article – Clinical Oncology
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Abstract

Background

Breast cancer is the most common cancer in women. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway transmits apoptotic signals. Novel anticancer agents that activate this system are in clinical development, including anti-breast cancer.

Methods

The tissue microarray technique was applied. We used an array of breast cancer tissues from a large group of patients (>800) to assess the protein expression of TRAIL-R1, TRAIL-R2, the long isoform of FLICE-inhibitory protein and total FLICE-inhibitory protein (FLIPL and FLIPT). Disease-free survival was examined by Kaplan–Meier estimates and the log-rank test. The independence of prognostic factors was determined by Cox multivariate analysis.

Results

High intra-tumoral expression of all these proteins of the TRAIL pathway was found. The TRAIL receptors and FLIPL were not associated with survival. On univariate analysis, strong FLIPT expression was associated with a significantly better survival (p = 0.001). On multivariate analysis using the Cox proportional hazards model, FLIPT phenotype was significantly associated with a good prognosis in this series (HR 0.52, 95 % CI 0.35–0.78, p = 0.039). Results indicate that this association is valid for all the biological subtypes of breast cancer. The expression of FLIPT was especially high in the luminal subtype, known for its good prognosis.

Conclusions

These findings support the use of agonistic TRAIL antibodies and drugs targeting FLIP in breast cancer patients. Over-expression of FLIPT but not TRAIL-R1, TRAIL-R2 or FLIPL provides stage-independent prognostic information in breast cancer patients. This indicates a clinically less aggressive phenotype.

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Acknowledgments

We thank CRUK and all patients. We are grateful to R. Moss for technical assistance. The Research Foundation Stiftelsen Onkologiska Klinikens i Uppsala Forskningsfond has kindly supported this study.

Conflict of interest

We declare that we have no conflict of interest.

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Authors and Affiliations

  1. Section of Oncology, Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden

    Gustav J. Ullenhag

  2. Department of Oncology, Uppsala University Hospital, Entrance 78, 751 85, Uppsala, Sweden

    Gustav J. Ullenhag

  3. Academic Department of Clinical Oncology and Histopathology, Nottingham University Hospital, Hucknall Road, Nottingham, NG5 1PB, UK

    Ahmad Al-Attar, Abhik Mukherjee, Andrew R. Green, Ian O. Ellis & Lindy G. Durrant

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  1. Gustav J. Ullenhag
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  2. Ahmad Al-Attar
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  3. Abhik Mukherjee
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  5. Ian O. Ellis
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  6. Lindy G. Durrant
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Correspondence to Gustav J. Ullenhag.

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Ullenhag, G.J., Al-Attar, A., Mukherjee, A. et al. The TRAIL system is over-expressed in breast cancer and FLIP a marker of good prognosis. J Cancer Res Clin Oncol 141, 505–514 (2015). https://doi.org/10.1007/s00432-014-1822-0

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  • DOI: https://doi.org/10.1007/s00432-014-1822-0

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