Abstract
TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis upon binding to TRAIL receptors 1 and 2 (TRAIL-R1/DR4 and TRAIL-R2/DR5). TRAIL-R3 (DcR1) and TRAIL-R4 (DcR2) have no or only a truncated cytoplasmic death domain. Consequently, they cannot induce apoptosis and instead have been proposed to inhibit apoptosis induction by TRAIL. Agonists for the apoptosis-inducing TRAIL-R1 and TRAIL-R2 are currently tested in clinical trials. To determine the expression pattern of all surface-bound TRAIL receptors and their prognostic clinical value, we investigated tumour samples of 311 patients with breast cancer by immunohistochemistry. TRAIL receptor expression profiles were correlated with clinico-pathological data, disease-free survival and overall survival. TRAIL-R1 was more strongly expressed in better differentiated tumours, and correlated positively with surrogate markers of a better prognosis (hormone receptor status, Bcl-2, negative nodal status), but negatively with the expression of Her2/neu and the proliferation marker Ki67. In contrast, TRAIL-R2 and TRAIL-R4 expression correlated with higher tumour grades, higher Ki67 index, higher Her2/neu expression and a positive nodal status at the time of diagnosis, but with lower expression of Bcl-2. Thus, the TRAIL receptor expression pattern was predictive of nodal status. Patients with grade 1 and 2 tumours, who had TRAIL-R2 but no TRAIL-R1, showed a positive lymph node status in 47% of the cases. Vice versa, only 19% had a positive nodal status with high TRAIL-R1 but low TRAIL-R2. Most strikingly, TRAIL-R4 and -R2 expression negatively correlated with overall survival of breast cancer patients. Although TRAIL-R2 correlated with more aggressive tumour behaviour, mammary carcinoma could be sensitised to TRAIL-R2-induced apoptosis, suggesting that TRAIL-R2 might therefore be used to therapeutically target such tumours. Hence, determination of the TRAIL receptor expression profile may aid in defining which breast cancer patients have a higher risk of lymph node metastasis and worse overall survival and on the other hand will help to guide TRAIL-based tumour therapy.
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Abbreviations
- Bio-LZ-TRAIL:
-
Biotinylated LZ-TRAIL
- DD:
-
Death domain
- DED:
-
Death effector domain
- DFS:
-
Disease-free survival
- DISC:
-
Death-inducing signalling complex
- ER:
-
Estrogen receptor
- FADD:
-
Fas-associated death domain protein
- GPI:
-
Glycosyl-phospatidylinositol
- HCC:
-
Hepatocellular carcinoma
- Her2/neu:
-
Human epidermal growth factor receptor 2 oncogene
- NSCLC:
-
Non-small cell lung cancer
- PgR:
-
Progesterone receptor
- OS:
-
Overall survival
- TNF:
-
Tumour necrosis factor
- TRAIL:
-
TNF-related apoptosis-inducing ligand
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Acknowledgements
We thank Jutta Mohr, Bärbel Moos and Heiko Stahl for excellent technical assistance. Tom M. Ganten and R. Koschny are recipients of a scholarship from the Deutsche Forschungsgemeinschaft (DFG). This project was supported by the Tumorzentrum Heidelberg/Mannheim (T. M. Ganten and H. Walczak) and by a grant from Deutsche Krebshilfe (H. Walczak).
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The authors declare that they have no conflict of interests.
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Ganten, T.M., Sykora, J., Koschny, R. et al. Prognostic significance of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in patients with breast cancer. J Mol Med 87, 995–1007 (2009). https://doi.org/10.1007/s00109-009-0510-z
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DOI: https://doi.org/10.1007/s00109-009-0510-z