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Circulating RANKL and RANKL/OPG and Breast Cancer Risk by ER and PR Subtype: Results from the EPIC Cohort.

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark. Unit of Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark. Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France. Gustave Roussy, Villejuif, France. Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 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, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts. Cancer Risk Factors and Lifestyle Epidemiology Unit, Cancer Research and Prevention Institute, ISPO, Florence, Italy. Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy. Cancer Registry and Histopathology Department, "Civic- M.P Arezzo" Hospital, ASP Ragusa, Italy. Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy. Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands. MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom. 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. Unit of Nutrition and Cancer, IDIBELL, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain. 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. Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia, Spain. Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain. Navarra Public Health Institute, Pamplona, Spain. IdiSNA, Navarra Institute for Health Research, Pamplona, Spain. Public Health Division of Gipuzkoa, BioDonostia Health Research Istitute, San Sebastian, Spain. Cancer Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom. Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. International Agency for Research on Cancer, Lyon, France. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. r.fortner@dkfz.de.

Cancer prevention research (Philadelphia, Pa.). 2017;(9):525-534
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Abstract

Receptor activator of nuclear factor-kappa B (RANK)-RANK ligand (RANKL) signaling promotes mammary tumor development in experimental models. Circulating concentrations of soluble RANKL (sRANKL) may influence breast cancer risk via activation of RANK signaling; this may be modulated by osteoprotegerin (OPG), the decoy receptor for RANKL. sRANKL and breast cancer risk by hormone receptor subtype has not previously been investigated. A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. This study included 1,976 incident invasive breast cancer cases [estrogen receptor positive (ER+), n = 1,598], matched 1:1 to controls. Women were pre- or postmenopausal at blood collection. Serum sRANKL was quantified using an ELISA, serum OPG using an electrochemiluminescent assay. Risk ratios (RR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression. Associations between sRANKL and breast cancer risk differed by tumor hormone receptor status (Phet = 0.05). Higher concentrations of sRANKL were positively associated with risk of ER+ breast cancer [5th vs. 1st quintile RR 1.28 (95% CI, 1.01-1.63); Ptrend = 0.20], but not ER- disease. For both ER+ and estrogen and progesterone receptor positive (ER+PR+) breast cancer, results considering the sRANKL/OPG ratio were similar to those for sRANKL; we observed a suggestive inverse association between the ratio and ER-PR- disease [5th vs. 1st quintile RR = 0.60 (0.31-1.14); Ptrend = 0.03]. This study provides the first large-scale prospective data on circulating sRANKL and breast cancer. We observed limited evidence for an association between sRANKL and breast cancer risk. Cancer Prev Res; 10(9); 525-34. ©2017 AACR.

Methodological quality

Publication Type : Multicenter Study

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MeSH terms : Osteoprotegerin ; RANK Ligand