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

Sarink, Danja; Schöck, Helena; Johnson, Theron; Overvad, Kim; Holm, Marianne; Tjønneland, Anne; Boutron‐Ruault, Marie‐Christine; His, Mathilde; Kvaskoff, Marina; Boeing, Heiner; Λάγιου, Παγώνα; Papatesta, Eleni Maria; Trichopoulou, Antonia; Palli, Domenico; Pala, Valeria; Mattiello, Amalia; Tumino, Rosario; Sacerdote, Carlotta; Bueno-de-Mesquita, H. B.; Gils, Carla H. van; Peeters, Petra H.M.; Weiderpass, Elisabete; Agudo, Antonio; Sánchez, María‐José; Chirlaque, María‐Dolores; Ardanáz, Eva; Amiano, Pilar; Khaw, Kay Tee; Travis, Ruth C.; Dossus, Laure; Gunter, Marc J.; Rinaldi, Sabina; Merritt, Melissa A.; Riboli, Elio; Kaaks, Rudolf; Fortner, Renée T.

doi:10.1158/1940-6207.capr-17-0125

Cited by 30 publications

(33 citation statements)

References 49 publications

(80 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Intra-batch coefficients of variation were 14.4% for sRANKL, and 15.3% for OPG. Within-person reproducibility of sRANKL and OPG over one and 14 years observed in our study have been published previously [ 9 , 12 ], Spearman correlation coefficients were r = 0.85 and r = 0.75 for OPG and r = 0.60 and r = 0.38 for sRANKL over one and 14 years, respectively.…”

Section: Methodssupporting

confidence: 88%

“…We have previously shown that OPG concentrations are reproducible over one and 14 years ( r = 0.85 and r = 0.75 respectively) [ 9 ]. Reproducibility of sRANKL was lower ( r = 0.60 and r = 0.38 over one and 14-years, respectively) [ 12 ]. This indicates that a single sRANKL measurement may not be representative of longer-term exposure, and may lead to attenuation of risk estimates.…”

Section: Discussionmentioning

confidence: 99%

“…tumor characteristics. We have recently shown a positive association between OPG concentrations and risk of ER- breast cancer (tertile 3 vs. 1 RR = 1.93 [95% CI 1.24–3.02]; p trend = 0.03) [ 9 ], whereas higher sRANKL concentrations were associated with risk of ER+ disease (quintile 5 vs. 1 RR 1.28 [95%CI 1.01–1.63]; p trend 0.20) [ 12 ]. Results from our current study indicate circulating concentrations of OPG and sRANKL may impact cancer risk and mortality differently, though further studies are required to more fully understand the underlying mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…The breast cancer cases in this study were part of a case-control study nested within the EPIC cohort. The study design and methods have been described previously [ 9 , 12 , 15 ]. Briefly, women diagnosed with a first invasive breast cancer between blood collection (ranging from 1992 to 2000 between centers) and completion of last follow-up for breast cancer incidence at the time the case-control study was initiated (ranging from 2003 to 2006 between centers) were included (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…The proportional hazards assumption was assessed using Schoenfeld residuals [ 18 ]. Based on our previous work on breast cancer risk showing significant heterogeneity by hormone receptor status [ 9 , 12 ], and the oversampling of ER- cases after 2004, we decided a priori to evaluate associations for mortality both overall and by ER status. Similarly, confounders were selected a priori.…”

Section: Methodsmentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2018

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Methodssupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

Changes in adiposity over the life course and gene expression in postmenopausal women

2022

View full text Add to dashboard Cite

Background Early life adiposity and changes in adiposity over the life course are associated with mammographic breast density among postmenopausal women. However, the underlying mechanisms are unknown; therefore, we comprehensively examined the associations of early life body mass index (BMI) and changes in BMI from ages 10, 18 to age at mammogram with growth factor, RANK pathway, and sex hormone gene expression in 372 postmenopausal women. Methods We estimated early life BMI at age 10 using the validated 9‐level Stunkard pictogram. We calculated BMI at other ages (18, 30, and current age at mammogram) by dividing weight in kilograms at these ages with height in meters squared. Sequencing for gene expression was performed using the NanoString nCounter system. After adjusting for confounders, we estimated associations using multivariable linear regressions. Results A 10 kg/m 2 increase in early life BMI at age 10 was associated with a 17.2% decrease in RANKL gene expression (95% confidence interval [CI] = −30.8, −0.9) but was not associated with changes in other markers. BMI changes from ages 10, 18 to age at mammogram were associated with an increase in BMP2 and decreases in RANK, RANKL, and TNFRSF13B gene expression but were not associated with gene expression of other markers. A 10 kg/m 2 increase in early life BMI from age 10 to current age was associated with a 7.8% increase in BMP2 (95% CI = −1.4, 17.8), an 8.5% decrease in RANK (95% CI = −13.9, −2.8), a 10.4% decrease in RANKL (95% CI = −16.9, −3.3), and an 8.5% decrease in TNFRSF13B gene expression (95% CI = −13.8, −2.8). Conclusion The results provide new insights into the biological mechanisms underlying the associations of adiposity changes from early life to adulthood and early life adiposity with mammographic breast density in postmenopausal women.

show abstract

OPG is associated with thyroid nodule development in type 2 diabetes

Huang

Niu

Zhang

et al. 2022

Clinical Laboratory Analysis

View full text Add to dashboard Cite

Background Thyroid nodule prevalence is increasing lately, especially in diabetes, but the mechanism of which is not clear. In this study, we investigated if osteoprotegerin (OPG) is involved in the pathogenesis of thyroid nodules in diabetes. Methods A total of 7568 individuals with detailed information and ultrasound examination results were studied for the prevalence of thyroid nodules. Among them, 1883 were with type 2 diabetes and 5685 were non‐diabetic. Then, 1120 individuals were randomly selected for the measurement of OPG. Diabetic rats were made by feeding a high‐fat‐high‐fructose diet for 28 weeks. Rats fed with a normal diet were as controls. Fresh thyroid tissues were obtained and fixed, dehydrated, and embedded in paraffin for hematoxylin‐eosin staining and observing pathological changes. qPCR and western blot were used to detect OPG expression in rat thyroid tissues. Results We found that HbA1c is an independent risk factor for thyroid nodules (Exp [ β ] = 1.158, p < 0.001). The prevalence of thyroid nodules in type 2 diabetes was higher than that in non‐diabetes (53.9% vs. 46.7%, p < 0.001). Serum OPG levels were significantly elevated in the diabetes group than in the non‐diabetes group (3160.17 pg/ml vs. 2819.39 pg/ml, p < 0.01). The expression of OPG increased significantly in the thyroid tissues of diabetic rats. Conclusion Osteoprotegerin may be associated with thyroid nodule development in diabetes.

show abstract

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

Cited by 30 publications

References 49 publications

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

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

Changes in adiposity over the life course and gene expression in postmenopausal women

OPG is associated with thyroid nodule development in type 2 diabetes

Contact Info

Product

Resources

About