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

• Published in: EBioMedicine 2015-10, Vol.2 (10), p.1331-1339
• Main Authors: Widschwendter, Martin, Burnell, Matthew, Fraser, Lindsay, Rosenthal, Adam N., Philpott, Sue, Reisel, Daniel, Dubeau, Louis, Cline, Mark, Pan, Yang, Yi, Ping-Cheng, Gareth Evans, D., Jacobs, Ian J., Menon, Usha, Wood, Charles E., Dougall, William C.
• Format: Article
• Language: English
• Subjects: Animals; BRCA1 and BRCA2 mutations; Breast cancer; Cancer prevention; Carcinogenesis; Case-Control Studies; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Female; Gene Expression Regulation, Neoplastic; Genes, BRCA1; Genes, BRCA2; Germ-Line Mutation; Hereditary Breast and Ovarian Cancer Syndrome - blood; Hereditary Breast and Ovarian Cancer Syndrome - genetics; Hereditary Breast and Ovarian Cancer Syndrome - metabolism; Heterozygote; Hormones - blood; Humans; Macaca fascicularis; Mutation; OPG; Osteoprotegerin - blood; Osteoprotegerin - metabolism; Patient Outcome Assessment; Postmenopause; RANK Ligand - blood; RANK Ligand - metabolism; RANKL; Risk Factors
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2015.08.037

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