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

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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12916-017-0786-8) contains supplementary material, which is available to authorized users.