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EBioMedicine. 2015 Sep 9;2(10):1331-9. doi: 10.1016/j.ebiom.2015.08.037. eCollection 2015 Oct.

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

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Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London WC1E 6AU, UK.
Department of Pathology, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Department of Molecular Sciences, Amgen Inc, Seattle, WA 98119, USA.
Department of Genomic Medicine, Institute of Human Development, University of Manchester, St. Mary's Hospital, Manchester M13 9WL, UK.
Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London WC1E 6AU, UK ; The University of New South Wales, UNSW, Sydney, NSW 2052, Australia.
Therapeutic Innovation Unit (TIU), Amgen Inc., Seattle, WA 98119, USA.


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.


BRCA1 and BRCA2 mutations; Breast cancer; Cancer prevention; Carcinogenesis; OPG; RANKL

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