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Osteoprotegerin and breast cancer risk by hormone receptor subtype: a nested case-control study in the EPIC cohort

Fortner RT 1 , Sarink D 2 , Schock H 2 , Johnson T 2 , Tjønneland A 3 , Olsen A 3 Show all authors , Overvad K 4 , Affret A 5 , His M 5 , Boutron-Ruault MC 5 , Boeing H 6 , Trichopoulou A 7 , Naska A 7 , Orfanos P 7 , Palli D 8 , Sieri S 9 , Mattiello A 10 , Tumino R 11 , Ricceri F 12 , Bueno-de-Mesquita HB 13 , Peeters PH 14 , Van Gils CH 14 , Weiderpass E 15 , Lund E 15 , Quirós JR 16 , Agudo A 17 , Sánchez MJ 18 , Chirlaque MD 19 , Ardanaz E 19 , Dorronsoro M 20 , Key T 21 , Khaw KT 22 , Rinaldi S 23 , Dossus L 23 , Gunter M 23 , Merritt MA 24 , Riboli E 24 , Kaaks R 2

Affiliations 

  • 1 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany. r.fortner@dkfz.de
  • 2 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany
  • 3 Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 4 Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark
  • 5 Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France
  • 6 Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
  • 7 Hellenic Health Foundation, Athens, Greece
  • 8 Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy
  • 9 Epidemiology and Prevention Unit, Department of Preventive & Predictive Medicine Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  • 10 Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy
  • 11 Cancer Registry and Histopathology Unit, "Civic - M.p.Arezzo" Hospital, ASP Ragusa, Italy
  • 12 Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco (TO), Italy
  • 13 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
  • 14 Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
  • 15 Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
  • 16 Public Health Directorate, Asturias, Spain
  • 17 Unit of Nutrition and Cancer. Cancer Epidemiology Research Program. Catalan Institute of Oncology-IDIBELL. L'Hospitalet de Llobregat, Barcelona, Spain
  • 18 Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs. GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain
  • 19 CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
  • 20 Public Health Direction and Biodonostia Research Institute CIBERESP, Basque Regional Health Department, San Sebastian, Spain
  • 21 Nuffield Department of Population Health, University of Oxford, Oxford, UK
  • 22 Cancer Epidemiology Unit, University of Cambridge, Cambridge, UK
  • 23 International Agency for Research on Cancer, Lyon, France
  • 24 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
BMC Med, 2017 02 08;15(1):26.
PMID: 28173834 DOI: 10.1186/s12916-017-0786-8

Abstract

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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]; p trend = 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 (p het = 0.97), and we observed no heterogeneity by HT use at blood collection (p het ≥ 0.43) or age at breast cancer diagnosis (p het ≥ 0.30).

CONCLUSIONS: 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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