Sarink, DanjaSchock, HelenaJohnson, TheronOvervad, KimHolm, MarianneTjønneland, AnneBoutron-Ruault, Marie-ChristineHis, MathildeKvaskoff, MarinaBoeing, HeinerLagiou, PagonaPapatesta, Eleni-MariaTrichopoulou, AntoniaPalli, DomenicoPala, ValeriaMattiello, AmaliaTumino, RosarioSacerdote, CarlottaBueno-de-Mesquita, H B Asvan Gils, Carla HPeeters, Petra HWeiderpass, ElisabeteAgudo, AntonioSanchez-Perez, Maria-JoseChirlaque, Maria-DoloresArdanaz, EvaAmiano, PilarKhaw, Kay TeeTravis, RuthDossus, LaureGunter, MarkRinaldi, SabinaMerritt, MelissaRiboli, ElioKaaks, RudolfFortner, Renée T2023-01-252023-01-252017-07-12http://hdl.handle.net/10668/11398Receptor 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.enAdultAgedBreastBreast NeoplasmsCase-Control StudiesFemaleFollow-Up StudiesHumansIncidenceMiddle AgedOsteoprotegerinProspective StudiesRANK LigandReceptors, EstrogenReceptors, ProgesteroneRisk Factorsresearch article28701332open access10.1158/1940-6207.CAPR-17-01251940-6215PMC5603271https://europepmc.org/articles/pmc5603271?pdf=renderhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603271/pdf