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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.

Author information

1
Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London WC1E 6AU, UK.
2
Department of Pathology, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
3
Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
4
Department of Molecular Sciences, Amgen Inc, Seattle, WA 98119, USA.
5
Department of Genomic Medicine, Institute of Human Development, University of Manchester, St. Mary's Hospital, Manchester M13 9WL, UK.
6
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.
7
Therapeutic Innovation Unit (TIU), Amgen Inc., Seattle, WA 98119, USA.

Abstract

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.

KEYWORDS:

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

PMID:
26629528
PMCID:
PMC4634624
DOI:
10.1016/j.ebiom.2015.08.037
[Indexed for MEDLINE]
Free PMC Article

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