Fortner, Renée TSarink, DanjaSchock, HelenaJohnson, TheronTjønneland, AnneOlsen, AnjaOvervad, KimAffret, AurélieHis, MathildeBoutron-Ruault, Marie-ChristineBoeing, HeinerTrichopoulou, AntoniaNaska, AndronikiOrfanos, PhilipposPalli, DomenicoSieri, SabinaMattiello, AmaliaTumino, RosarioRicceri, FulvioBueno-de-Mesquita, H BasPeeters, Petra H MVan Gils, Carla HWeiderpass, ElisabeteLund, EilivQuirós, J RamónAgudo, AntonioSanchez-Perez, Maria-JoseChirlaque, María-DoloresArdanaz, EvaDorronsoro, MirenKey, TimKhaw, Kay-TeeRinaldi, SabinaDossus, LaureGunter, MarcMerritt, Melissa ARiboli, ElioKaaks, Rudolf2017-05-182017-05-182017-02-08Fortner R, Sarink D, Schock H, Johnson T, Tjønneland A, Olsen A et al. Osteoprotegerin and breast cancer risk by hormone receptor subtype: a nested case-control study in the EPIC cohort. BMC Medicine. 2017;15(1)http://hdl.handle.net/10668/2647BACKGROUND: 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.enBreast cancerNeoplasias de la mamaEstrogen receptorHormone receptorOsteoprotegerinOsteoprotegerinaProgesterone receptorReceptores de progesteronaReceptores estrogénicosReceptores de hormonasRANK axisMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Breast NeoplasmsMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::DNA-Binding Proteins::Receptors, Cytoplasmic and Nuclear::Receptors, Steroid::Receptors, EstrogenMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Immunologic::Receptors, Cytokine::Receptors, Tumor Necrosis Factor::Tumor Necrosis Factor Decoy Receptors::OsteoprotegerinMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors::Receptors, Cytoplasmic and Nuclear::Receptors, Steroid::Receptors, ProgesteroneMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Immunologic::Receptors, Cytokine::Receptors, Tumor Necrosis Factor::Receptor Activator of Nuclear Factor-kappa BMedical Subject Headings::Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control StudiesMedical Subject Headings::Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Prospective StudiesMedical Subject Headings::Phenomena and Processes::Reproductive and Urinary Physiological Phenomena::Reproductive Physiological Phenomena::Climacteric::Menopause::PostmenopauseMedical Subject Headings::Health Care::Environment and Public Health::Public Health::Epidemiologic Factors::Causality::Risk Factorsresearch article28173834open access10.1186/s12916-017-0786-81741-7015PMC5297136