Circulating RANKL and RANKL/OPG and breast cancer risk by ER and PR subtype: Results from the EPIC cohort

Receptor 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. <p>A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. This study included 1976 incident invasive breast cancer cases (estrogen receptor positive (ER+), n=1598), matched 1:1 to controls. Women were pre- or postmenopausal at blood collection. Serum sRANKL was quantified using an enzyme-linked immunosorbent assay, serum OPG using an electrochemiluminescent assay. Risk ratios (RRs) and 95% confidence intervals (95%CIs) were calculated using conditional logistic regression.</p> <p>Associations between sRANKL and breast cancer risk differed by tumor hormone receptor status (p_het 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]; p_trend 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 (5^th vs. 1^st quintile RR 0.60 [0.31-1.14]; p_trend 0.03).</p> <p>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.

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