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Osteoprotegerin (OPG), the endogenous inhibitor of receptor activator of NF-κB ligand (RANKL), is dysregulated in BRCA mutation carriers

Widschwendter, M; Burnell, M; Fraser, L; Rosenthal, AN; Philpott, S; Reisel, D; Dubeau, L; ... Dougall, WC; + view all (2015) Osteoprotegerin (OPG), the endogenous inhibitor of receptor activator of NF-κB ligand (RANKL), is dysregulated in BRCA mutation carriers. EBioMedicine , 2 (10) pp. 1331-1339. 10.1016/j.ebiom.2015.08.037. Green open access

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

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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.

Type: Article
Title: Osteoprotegerin (OPG), the endogenous inhibitor of receptor activator of NF-κB ligand (RANKL), is dysregulated in BRCA mutation carriers
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ebiom.2015.08.037
Publisher version: http://dx.doi.org/10.1016/j.ebiom.2015.08.037
Additional information: © 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: BRCA1 and BRCA2 mutations, Breast cancer, Cancer prevention, Carcinogenesis, OPG, RANKL
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health > Womens Cancer
URI: https://discovery.ucl.ac.uk/id/eprint/1473333
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