Prognostic significance of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in patients with breast cancer
Autor: | Ulrich Mansmann, Hans-Peter Sinn, Tom M. Ganten, Sebastian Aulmann, Jaromir Sykora, Wolfgang Stremmel, Ronald Koschny, Henning Walczak, Emanuela M Batke |
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Rok vydání: | 2009 |
Předmět: |
Adult
Pathology medicine.medical_specialty Programmed cell death Receptor expression Apoptosis Breast Neoplasms Kaplan-Meier Estimate Disease-Free Survival Breast cancer Cell Line Tumor Drug Discovery Biomarkers Tumor medicine Animals Humans Protein Isoforms Genetics (clinical) Aged Aged 80 and over Antibiotics Antineoplastic business.industry Reproducibility of Results Cancer Middle Aged Prognosis medicine.disease Immunohistochemistry Molecular medicine Receptors TNF-Related Apoptosis-Inducing Ligand Doxorubicin Tissue Array Analysis Hormone receptor Cancer research Molecular Medicine Female Breast disease business |
Zdroj: | Journal of Molecular Medicine. 87:995-1007 |
ISSN: | 1432-1440 0946-2716 |
Popis: | 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. |
Databáze: | OpenAIRE |
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