Abstract
BACKGROUND: Emerging evidence supports a role of the receptor activator of NF-κB (RANK) pathway in normal mammary gland development and breast carcinogenesis. Osteoprotegerin (OPG) is the endogenous decoy receptor for RANK-ligand (RANKL), which inhibits RANK-signaling. Whether OPG may be a biomarker of breast cancer risk remains unclear. METHODS: We evaluated the association between plasma OPG and breast cancer risk in a case (n = 297)-control (n = 297) study nested within the Nurses' Health Study II. Cases were women who were cancer-free and premenopausal at blood collection who developed invasive breast cancer. OPG was quantified using an ELISA. Conditional logistic regression was used to estimate multivariable odds ratios (OR) and 95% confidence intervals (CI) for the association between OPG levels and breast cancer risk, adjusting for potential confounders. Unconditional logistic regression, additionally adjusting for matching factors, was used for stratified analyses. RESULTS: Overall, there was no substantial evidence for an association between plasma OPG levels and breast cancer risk, although the point estimate for the highest (vs. lowest) quartile was below 1 (OR = 0.78; 95% CI, 0.46-1.33; P (trend) = 0.30). There was no evidence of heterogeneity by various reproductive, hormonal, or tumor characteristics, including hormone receptor status and grade (all P (heterogeneity) ≥ 0.17). CONCLUSIONS: Findings from this prospective study do not provide substantial evidence for an association between circulating OPG and breast cancer risk among premenopausal women; however, we were underpowered in stratified analyses. IMPACT: Results do not provide strong evidence for OPG as a potential biomarker of breast cancer risk among premenopausal women.