Receptor activator of nuclear factor kB ligand, osteoprotegerin, and risk of death following a breast cancer diagnosis: results from the EPIC cohort

Abstract

BackgroundReceptor activator of nuclear factor kappa-B (RANK)-signaling is involved in tumor growth and spread in experimental models. Binding of RANK ligand (RANKL) to RANK activates signaling, which is inhibited by osteoprotegerin (OPG). We have previously shown that circulating soluble RANKL (sRANKL) and OPG are associated with breast cancer risk. Here we extend these findings to provide the first data on pre-diagnosis concentrations of sRANKL and OPG and risk of breast cancer-specific and overall mortality after a breast cancer diagnosis.MethodsTwo thousand six pre- and postmenopausal women with incident invasive breast cancer (1620 (81%) with ER+ disease) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were followed-up for mortality. Pre-diagnosis concentrations of sRANKL and OPG were quantified in baseline serum samples using an enzyme-linked immunosorbent assay and electrochemiluminescent assay, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific and overall mortality were calculated using Cox proportional hazards regression models.ResultsEspecially in women with ER+ disease, higher circulating OPG concentrations were associated with higher risk of breast cancer-specific (quintile 5 vs 1 HR 1.77 [CI 1.03, 3.04]; ptrend 0.10) and overall mortality (q5 vs 1 HR 1.39 [CI 0.94, 2.05]; ptrend 0.02). sRANKL and the sRANKL/OPG ratio were not associated with mortality following a breast cancer diagnosis.ConclusionsHigh pre-diagnosis endogenous concentrations of OPG, the decoy receptor for RANKL, were associated with increased risk of death after a breast cancer diagnosis, especially in those with ER+ disease. These results need to be confirmed in well-characterized patient cohorts.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4887-3) contains supplementary material, which is available to authorized users.

RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives

“…Sarink et al have recently conducted a large-scale prospective study on 2006 pre- and postmenopausal patients with incident invasive breast cancer participating in the EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. Importantly, the authors showed that higher pre-diagnosis circulating OPG concentrations - assessed by an electrochemiluminescent assay - are associated with a greater risk of breast cancer-specific and overall mortality, especially in ER-positive breast cancer patients [137]. Similarly, Rachner et al showed that higher OPG serum levels - detected by ELISA - are associated with a significantly higher risk of death from breast cancer in patients with primary, non-metastatic breast cancer.…”

“…quantitative PCR, immunohistochemistry). According to the recent findings from Sarink et al [137] and Rachner et al [138], it is also possible that OPG circulating concentrations at diagnosis represent a more informative measure for breast cancer prognosis and mortality than OPG expression in tumor tissue. Further investigations in well-defined patient cohorts (e.g.…”

Reproductive and Lifestyle Factors and Circulating sRANKL and OPG Concentrations in Women: Results from the EPIC Cohort

“…Studies in experimental animal models have shown that the RANK axis plays an important role in a number of processes including bone turnover, immune response, cardiovascular disease, and breast development in pregnancy, as well as development and progression of breast cancer (1)(2)(3). With respect to breast cancer, we (4)(5)(6) and others (7)(8)(9)(10) have observed associations between circulating concentrations of RANK axis members and breast cancer risk and prognosis. Following development of an antibody for RANKL, denosumab, there is increasing interest in RANKL and OPG in relation to breast cancer prevention and treatment.…”

Peripheral Blood-Based Biopsy for Breast Cancer Risk Prediction and Early Detection

“…Another study identified high serum OPG levels to be mainly associated with increased risk for ER-BC (39). On the other hand, a large scale investigation with a cohort of 1,976 incident invasive BC cases, of which 1,598 were ER+, showed limited evidence for correlating circulating RANKL levels with BC risk (40). Notably, and despite the availability of a myriad of BC studies in the proteomics literature (41,42), the field is still lacking invalidated protein markers for both BC risk prediction and early detection.…”