RANK and RANKL Expression in Tumors of Patients with Early Breast Cancer

Abstract

Introduction

The receptor activator of nuclear factor-κB (RANK) pathway was associated with the pathogenesis of breast cancer. Several studies attempted to link the RANK/RANKL pathway to prognosis; however, with inconsistent outcomes. We aimed to further contribute to the knowledge about RANK/RANKL as prognostic factors in breast cancer. Within this study, protein expression of RANK and its ligand, RANKL, in the tumor tissue was analyzed in association with disease-free survival (DFS) and overall survival (OS) in a study cohort of patients with early breast cancer.

Patients and Methods

607 samples of female primary and early breast cancer patients from the Bavarian Breast Cancer Cases and Controls Study were analyzed to correlate the RANK and RANKL expression with DFS and OS. Therefore, expression was quantified using immunohistochemical staining of a tissue microarray. H-scores were determined with the cut-off value of 8.5 for RANK and 0 for RANKL expression, respectively.

Results

RANK and RANKL immunohistochemistry were assessed by H-score. Both biomarkers did not correlate (ρ = −0.04). According to molecular subtypes, triple-negative tumors and HER2-positive tumors showed a higher number of RANK-positive tumors (H-score ≥ 8.5), however, no subtype-specific expression of RANKL could be detected. Higher RANKL expression tended to correlate with a better prognosis. However, RANK and RANKL expression could not be identified as statistically significant prognostic factors within the study cohort.

Conclusions

Tumor-specific RANK and RANKL expressions are not applicable as prognostic factors for DFS and OS, but might be associated with subtype-specific breast cancer progression.

Zusammenfassung

Einleitung

Es gibt eine Verbindung zwischen dem Rezeptor-Aktivator des Nuklearfaktor-κB-(RANK-)Signalwegs und der Pathogenese von Brustkrebs. Mehrere Studien haben versucht, eine Assoziation zwischen dem RANK-/RANKL-Signalweg und der Krankheitsprognose herzustellen, aber die bisher erzielten Ergebnisse sind uneinheitlich. Ziel dieser Arbeit war es, weitere Kenntnisse zur Expression von RANK/RANKL als prognostischer Faktor beim Mammakarzinom zu sammeln. Dazu wurde die Proteinexpression von RANK und seines Liganden, RANKL, im Tumorgewebe einer Studienpopulation von Patientinnen mit frühem Brustkrebs analysiert und auf eine Assoziation mit dem krankheitsfreien Überleben (DFS) und Gesamtüberleben (OS) geprüft.

Patientinnen und Methoden

Analysiert wurden 607 Proben, die Patientinnen mit Primärtumoren und frühem Brustkrebs in einer bayerischen Brustkrebs-Fall-Kontroll-Studie entnommen wurden. Es wurde geprüft, ob es eine Korrelation zwischen RANK- und RANKL-Expression und DFS and OS gibt. Zur Quantifizierung der Expression wurden Tissue-Micro-Arrays einer immunhistochemischen Färbung unterzogen. Die H-Scores wurden bestimmt. Der jeweilige Cut-off-Wert war 8,5 für RANK- bzw. 0 für RANKL-Expression.

Ergebnisse

RANK- und RANKL-Immunhistochemie wurden mithilfe des H-Scores beurteilt. Es gab für keinen der 2 Biomarker eine Korrelation (ρ = −0,04). Bei den Subtypen tripelnegativer Tumor und HER2-positiver Tumor fand sich eine höhere Anzahl RANK-positiver Tumoren (H-Score ≥ 8,5), aber es war keine subtypspezifische RANKL-Expression nachzuweisen. Eine höhere RANKL-Expression korrelierte tendenziell mit einer besseren Prognose. RANK- und RANKL-Expression waren aber in dieser Patientinnenpopulation nicht statistisch signifikante prognostische Faktoren.

Schlussfolgerungen

Die tumorspezifische RANK- und RANKL-Expression eignet sich nicht als prognostischer Faktor für DFS und OS, könnte aber mit der Krankheitsprogression bestimmter Brustkrebs-Subtypen assoziiert sein.

Keywords

breast cancer - RANK - RANKL - prognosis - immunohistochemistry

Schlüsselwörter

Brustkrebs - RANK - RANKL - Prognose - Immunohistochemie

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