Osteoprotegerin and breast cancer risk by hormone receptor subtype: a nested case-control study in the EPIC cohort.
Circulating osteoprotegerin (OPG), a member of the receptor activator of nuclear factor kappa-B (RANK) axis, may influence breast cancer risk via its role as the decoy receptor for both the RANK ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Circulating OPG and breast cancer risk has been examined in only one prior study.



A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 2008 incident invasive breast cancer cases (estrogen receptor (ER)+, n = 1622; ER-, n = 386), matched 1:1 to controls, were included in the analysis. Women were predominantly postmenopausal at blood collection (77%); postmenopausal women included users and non-users of postmenopausal hormone therapy (HT). Serum OPG was quantified with an electrochemiluminescence assay. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression.



The associations between OPG and ER+ and ER- breast cancer differed significantly. Higher concentrations of OPG were associated with increased risk of ER- breast cancer (top vs. bottom tertile RR = 1.93 [95% CI 1.24-3.02]; ptrend= 0.03). We observed a suggestive inverse association for ER+ disease overall and among women premenopausal at blood collection. Results for ER- disease did not differ by menopausal status at blood collection (phet= 0.97), and we observed no heterogeneity by HT use at blood collection (phet≥ 0.43) or age at breast cancer diagnosis (phet≥ 0.30).



This study provides the first prospective data on OPG and breast cancer risk by hormone receptor subtype. High circulating OPG may represent a novel risk factor for ER- breast cancer.
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany. r.fortner@dkfz.de.
Renée T
RT
Fortner
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany.
Danja
D
Sarink
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany.
Helena
H
Schock
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany.
Theron
T
Johnson
Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark.
Anne
A
Tjønneland
Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark.
Anja
A
Olsen
Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.
Kim
K
Overvad
Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.|Gustave Roussy, F-94805, Villejuif, France.
Aurélie
A
Affret
Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.|Gustave Roussy, F-94805, Villejuif, France.
Mathilde
M
His
Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.|Gustave Roussy, F-94805, Villejuif, France.
Marie-Christine
MC
Boutron-Ruault
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
Heiner
H
Boeing
Hellenic Health Foundation, Athens, Greece.|WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece.
Antonia
A
Trichopoulou
Hellenic Health Foundation, Athens, Greece.|WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece.
Androniki
A
Naska
Hellenic Health Foundation, Athens, Greece.|WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece.
Philippos
P
Orfanos
Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy.
Domenico
D
Palli
Epidemiology and Prevention Unit, Department of Preventive & Predictive Medicine Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Sabina
S
Sieri
Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
Amalia
A
Mattiello
Cancer Registry and Histopathology Unit, "Civic - M.p.Arezzo" Hospital, ASP Ragusa, Italy.
Rosario
R
Tumino
Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco (TO), Italy.|Unit of Cancer Epidemiology, Department of Medical Sciences, University of Turin, Turin, Italy.
Fulvio
F
Ricceri
Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.|Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.|Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
H Bas
HB
Bueno-de-Mesquita
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.|MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK.
Petra H M
PH
Peeters
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.
Carla H
CH
Van Gils
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.|Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland.
Elisabete
E
Weiderpass
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.
Eiliv
E
Lund
Public Health Directorate, Asturias, Spain.
J Ramón
JR
Quirós
Unit of Nutrition and Cancer. Cancer Epidemiology Research Program. Catalan Institute of Oncology-IDIBELL. L'Hospitalet de Llobregat, Barcelona, Spain.
Antonio
A
Agudo
Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs. GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.|CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
Maria-José
MJ
Sánchez
CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.|Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia, Spain.|Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain.
María-Dolores
MD
Chirlaque
CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.|Navarra Public Health Institute, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
Eva
E
Ardanaz
Public Health Direction and Biodonostia Research Institute CIBERESP, Basque Regional Health Department, San Sebastian, Spain.
Miren
M
Dorronsoro
Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Tim
T
Key
Cancer Epidemiology Unit, University of Cambridge, Cambridge, UK.
Kay-Tee
KT
Khaw
International Agency for Research on Cancer, Lyon, France.
Sabina
S
Rinaldi
International Agency for Research on Cancer, Lyon, France.
Laure
L
Dossus
International Agency for Research on Cancer, Lyon, France.
Marc
M
Gunter
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
Melissa A
MA
Merritt
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
Elio
E
Riboli
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany.
Rudolf
R
Kaaks
D001943:Breast Neoplasms / Q000097:blood*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008875:Middle Aged; D053244:Osteoprotegerin / Q000097:blood*; D011446:Prospective Studies; D012307:Risk Factors
D053244:Osteoprotegerin
Breast cancer; Estrogen receptor; Hormone receptor; Osteoprotegerin; Progesterone receptor; RANK axis