Receptor activator of nuclear factor kB ligand, osteoprotegerin, and risk of death following a breast cancer diagnosis: results from the EPIC cohort

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Title: Receptor activator of nuclear factor kB ligand, osteoprotegerin, and risk of death following a breast cancer diagnosis: results from the EPIC cohort
Authors: Sarink, D
Schock, H
Johnson, T
Chang-Claude, J
Overvad, K
Olsen, A
Tjonneland, A
Arveux, P
Fournier, A
Kvaskoff, M
Boeing, H
Karakatsani, A
Trichopoulou, A
La Vecchia, C
Masala, G
Agnoli, C
Panico, S
Tumino, R
Sacerdote, C
Van Gils, CH
Peeters, PHM
Weiderpass, E
Agudo, A
Rodriguez-Barranco, M
Maria Huerta, J
Ardanaz, E
Gil, L
Kaw, KT
Schmidt, JA
Dossus, L
His, M
Aune, D
Riboli, E
Kaaks, R
Fortner, RT
Item Type: Journal Article
Abstract: Background Receptor activator of nuclear factor kappa-B (RANK)-signaling is involved in tumor growth and spread in experimental models. Binding of RANK ligand (RANKL) to RANK activates signaling, which is inhibited by osteoprotegerin (OPG). We have previously shown that circulating soluble RANKL (sRANKL) and OPG are associated with breast cancer risk. Here we extend these findings to provide the first data on pre-diagnosis concentrations of sRANKL and OPG and risk of breast cancer-specific and overall mortality after a breast cancer diagnosis. Methods Two thousand six pre- and postmenopausal women with incident invasive breast cancer (1620 (81%) with ER+ disease) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were followed-up for mortality. Pre-diagnosis concentrations of sRANKL and OPG were quantified in baseline serum samples using an enzyme-linked immunosorbent assay and electrochemiluminescent assay, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific and overall mortality were calculated using Cox proportional hazards regression models. Results Especially in women with ER+ disease, higher circulating OPG concentrations were associated with higher risk of breast cancer-specific (quintile 5 vs 1 HR 1.77 [CI 1.03, 3.04]; ptrend 0.10) and overall mortality (q5 vs 1 HR 1.39 [CI 0.94, 2.05]; ptrend 0.02). sRANKL and the sRANKL/OPG ratio were not associated with mortality following a breast cancer diagnosis. Conclusions High pre-diagnosis endogenous concentrations of OPG, the decoy receptor for RANKL, were associated with increased risk of death after a breast cancer diagnosis, especially in those with ER+ disease. These results need to be confirmed in well-characterized patient cohorts.
Issue Date: 22-Oct-2018
Date of Acceptance: 2-Oct-2018
ISSN: 1471-2407
Publisher: BioMed Central
Journal / Book Title: BMC Cancer
Volume: 18
Copyright Statement: © 2018 The Author(s). Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
Keywords: Science & Technology
Life Sciences & Biomedicine
Breast cancer
and related factors
Serum biomarkers of endogenous exposures
Reproductive, hormonal, and related factors
1112 Oncology And Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Article Number: 1010
Appears in Collections:Faculty of Medicine
Epidemiology, Public Health and Primary Care

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