Plasma osteoprotegerin and breast cancer risk in BRCA1 and BRCA2 mutation carriers.

Lovisa Odén,Christian F Singer,Leonardo Salmena,Joanne Kotsopoulos,Tasnim Zaman,Mohammad Akbari,Steven A Narod,Ping Sun

doi:10.18632/oncotarget.13417

Lovisa Odén, Christian F Singer + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.13417

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Abstract

Emerging evidence suggests a role of receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) signaling in breast cancer development. Lower osteoprotegerin (OPG) levels, the endogenous decoy receptor for RANKL which competes with RANK for binding of RANKL, has been reported among BRCA mutation carriers. Whether low OPG levels contribute to the high breast cancer risk in this population is unknown. OPG concentrations were measured in plasma of 206 cancer-free BRCA mutation carriers using an enzyme-linked immunosorbent assay. Subjects were categorized as high vs. low based on the median of the entire cohort (95 ng/mL) and followed for a new diagnosis of breast cancer. Cumulative incidence by baseline plasma OPG concentration was estimated using Kaplan-Meier survival analysis. Cox proportional hazards models were used to estimate the adjusted hazard ratios for the association between plasma OPG and breast cancer risk. Over a mean follow-up period of 6.5 years (range 0.1–18.8 years), 18 incident breast cancer cases were observed. After ten years of follow-up, the cumulative incidence of breast cancer among women with low OPG was 21%, compared to 9% among women with high OPG (P-log rank = 0.046). After multivariate adjustment, women with high plasma OPG had a significantly decreased risk of developing breast cancer, compared to women with low OPG (HR = 0.25; 95%CI 0.08–0.78; P = 0.02). These data suggest that low OPG levels are associated with an increased risk of BRCA-associated breast cancer. Targeting RANK signalling may represent a plausible, non-surgical prevention option for BRCA mutation carriers.

Highlights

Women who inherit a deleterious mutation in one of the two breast cancer susceptibility genes, BRCA1 or BRCA2, face a high lifetime risk of breast cancer, compared to women in the general population [1,2,3]
Findings from the Women’s Health Initiative (WHI), a randomized placebocontrolled trial of hormone replacement therapy showed that combined therapy was associated with a significant increased risk of breast cancer [7] whereas the use of estrogen alone was associated with a decreased risk (HR = 0.77; 95%confidence intervals (CI) 0.62–0.95) [8]
We demonstrate a significant inverse relationship between plasma OPG levels and breast cancer risk among 206 women with an inherited BRCA1 or BRCA2 mutation

Summary

Introduction

Women who inherit a deleterious mutation in one of the two breast cancer susceptibility genes, BRCA1 or BRCA2, face a high lifetime risk of breast cancer, compared to women in the general population [1,2,3]. Widschwendter et al reported significantly lower mean circulating levels of osteoprotegerin (OPG), the endogenous decoy receptor for RANKL that antagonizes RANK/RANKL-mediated signaling, as well as higher progesterone levels among premenopausal BRCA mutation carriers compared to noncarrier controls [16, 17]. Together, these studies strongly suggest that a role for the progesterone-mediated RANK/ RANKL signaling pathway in the development of mammary carcinogenesis may be relevant in women with a BRCA mutation. Targeting aberrancies in RANKL signaling may represent a plausible, non-surgical chemoprevention option for this high-risk population

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