Abstract
BackgroundCirculating 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.MethodsA 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.ResultsThe 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).ConclusionsThis 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.
Highlights
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)
OPG binds RANKL as a decoy receptor, inhibiting the activation of RANK by RANKL and preventing the differentiation of bone marrow precursor cells to osteoclasts — cells that are central in the process of bone resorption [2]
In vitro studies suggest that OPG, again acting as a decoy receptor, binds to tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL), thereby preventing cancer cell death via apoptosis [7, 8]
Summary
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). OPG is expressed in other tissues, including the stomach, intestines, skin, liver, heart, lung, kidney, and breast. This expression across diverse tissue types indicates that its biologic functions may extend beyond bone metabolism. In vitro studies suggest that OPG, again acting as a decoy receptor, binds to TNF-related apoptosisinducing ligand (TRAIL), thereby preventing cancer cell death via apoptosis [7, 8]. OPG can induce cell proliferation and angiogenesis through a variety of cell surface receptors [5, 6]
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