title: Osteoprotegerin (OPG), The Endogenous Inhibitor of Receptor Activator of NF-κB Ligand (RANKL), is Dysregulated in BRCA Mutation Carriers.
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.
authors.affiliation: Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London WC1E 6AU, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
authors.affiliation: Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London WC1E 6AU, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Burnell
authors.affiliation: Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London WC1E 6AU, UK.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Fraser
authors.affiliation: Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London WC1E 6AU, UK.
authors.forename: Adam N
authors.initials: AN
authors.lastname: Rosenthal
authors.affiliation: Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London WC1E 6AU, UK.
authors.forename: Sue
authors.initials: S
authors.lastname: Philpott
authors.affiliation: Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London WC1E 6AU, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Reisel
authors.affiliation: Department of Pathology, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Dubeau
authors.affiliation: Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Cline
authors.affiliation: Department of Molecular Sciences, Amgen Inc, Seattle, WA 98119, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Molecular Sciences, Amgen Inc, Seattle, WA 98119, USA.
authors.forename: Ping-Cheng
authors.initials: PC
authors.lastname: Yi
authors.affiliation: Department of Genomic Medicine, Institute of Human Development, University of Manchester, St. Mary's Hospital, Manchester M13 9WL, UK.
authors.forename: D
authors.initials: D
authors.lastname: Gareth Evans
authors.affiliation: 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.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jacobs
authors.affiliation: Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London WC1E 6AU, UK.
authors.forename: Usha
authors.initials: U
authors.lastname: Menon
authors.affiliation: Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wood
authors.affiliation: Therapeutic Innovation Unit (TIU), Amgen Inc., Seattle, WA 98119, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Dougall
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000097:blood / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006728:Hormones / Q000097:blood; D006801:Humans; D008252:Macaca fascicularis; D009154:Mutation; D053244:Osteoprotegerin / Q000097:blood / Q000378:metabolism*; D063868:Patient Outcome Assessment; D017698:Postmenopause; D053245:RANK Ligand / Q000097:blood / Q000378:metabolism*; D012307:Risk Factors
chemical_list: D006728:Hormones; D053244:Osteoprotegerin; D053245:RANK Ligand
keywords: BRCA1 and BRCA2 mutations; Breast cancer; Cancer prevention; Carcinogenesis; OPG; RANKL