Osteoprotegerin (OPG), The Endogenous Inhibitor of Receptor Activator of NF-κB Ligand (RANKL), is Dysregulated in BRCA Mutation Carriers

• Osteoprotegerin (OPG) is the endogenous inhibitor of Receptor Activator of NF-κB Ligand (RANKL)
• RANKL has been shown to be crucially important in progesterone-mediated breast carcinogenesis
• Serum OPG is regulated by progesterone and low in BRCA1/2 mutation carriers
• Low serum OPG is associated with increased proliferation in the mammary gland
• Antiprogestogens or anti-RANKL antibody (denosumab) may be new strategies for breast cancer prevention in BRCA1/2 carriers.Preventing deadly cancers is a high priority of 21st century medicine. To find the most promising cancer causing targets which can be modulated using chemo-preventive drugs remains the biggest challenge. In this paper we show that OPG, which is the physiological antagonist of RANKL (a factor known to be crucially involved in breast carcinogenesis), is low in women who have inherited a gene mutation (i.e. in BRCA1 or 2) which puts them at extremely high risk of developing breast cancer. An antibody which mimics OPG might be a very attractive option in preventing breast cancer.

Breast cancer development in BRCA1/2 mutation carriers is a net consequence of cell-autonomous and cell nonautonomous factors which may serve as excellent targets for cancer prevention. In light of our previous data we sought to investigate the consequences of the BRCA-mutation carrier state on RANKL/osteoprotegerin (OPG) signalling.We analysed serum levels of RANKL, OPG, RANKL/OPG complex, oestradiol (E2), and progesterone (P) during menstrual cycle progression in 391 BRCA1/2-mutation carriers and 782 noncarriers. These studies were complemented by analyses of RANKL and OPG in the serum and mammary tissues of female cynomolgus macaques (n = 88) and serum RANKL and OPG in postmenopausal women (n = 150).BRCA-mutation carriers had lower mean values of free serum OPG in particular in BRCA1-mutation carriers (p = 0.018) compared with controls. Among BRCA1/2 mutation carriers, lower OPG levels were associated with germline mutation locations known to confer an increased breast cancer risk (p = 0.003). P is associated with low OPG levels in serum and tissue, particularly in BRCA-mutation carriers (rho = − 0.216; p = 0.002). Serum OPG levels were inversely correlated (rho = − 0.545, p < 0.001) with mammary epithelial proliferation measured by Ki67 expression and increased (p = 0.01) in postmenopause.The P–RANKL/OPG system is dysregulated in BRCA-mutation carriers. These and previously published data provide a strong rationale for further investigation of antiprogestogens or an anti-RANKL antibody such as denosumab for breast cancer prevention.