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BMC Cancer. 2018 Oct 22;18(1):1010. doi: 10.1186/s12885-018-4887-3.

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

Author information

1
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
2
Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.
3
Danish Cancer Society Research Center, Copenhagen, Denmark.
4
Breast and Gynaecologic Cancer Registry of Côte d'Or, Georges-François Leclerc Comprehensive Cancer Care Centre, Dijon, France.
5
Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.
6
Gustave Roussy, Villejuif, France.
7
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
8
Hellenic Health Foundation, Athens, Greece.
9
2nd Pulmonary Medicine Department, School of Medicine, National and Kapodistrian University of Athens, "ATTIKON" University Hospital, Haidari, Athens, Greece.
10
WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
11
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
12
Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute - ISP, Florence, Italy.
13
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
14
Dipartimento di Medicine Clinica e Chirurgia, Federico II University, Naples, Italy.
15
Cancer Registry and Histopathology Department, "Civic M.P.Arezzo" Hospital, Azienda Sanitaria Provinciale, Ragusa, Italy.
16
Unit of Cancer Epidemiology, Città della Salute e della Scienza University Hospital and Center for Cancer Prevention (CPO), Turin, Italy.
17
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
18
MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK.
19
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.
20
Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.
21
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
22
Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland.
23
Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
24
Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.
25
CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
26
Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
27
Navarra Public Health Institute, Pamplona, Spain.
28
IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
29
Public Health Division of Gipuzkoa, Biodonostia Health Research Institute, San Sebastian, Spain.
30
Cancer Epidemiology Unit, University of Cambridge, Cambridge, UK.
31
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
32
International Agency for Research on Cancer, Lyon, France.
33
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK.
34
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. r.fortner@dkfz.de.

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.

KEYWORDS:

Breast cancer; Epidemiology; Reproductive, hormonal, and related factors; Serum biomarkers of endogenous exposures

PMID:
30348163
PMCID:
PMC6196438
DOI:
10.1186/s12885-018-4887-3
[Indexed for MEDLINE]
Free PMC Article

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