title: Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer.
abstract: Breast cancer is the most common female cancer, affecting approximately one in eight women during their lifetime in North America and Europe. Receptor Activator of NF-kB Ligand (RANKL), its receptor RANK and the natural antagonist osteoprotegerin (OPG) are essential regulators of bone resorption. We have initially shown that RANKL/RANK are essential for hormone-driven mammary epithelial proliferation in pregnancy and RANKL/RANK have been implicated in mammary stem cell biology. Using genetic mouse-models, we and others identified the RANKL/RANK system as a key regulator of sex hormone, BRCA1-mutation, and oncogene-driven breast cancer and we proposed that RANKL/RANK might be involved in the initiation of breast tumors. We now report that in postmenopausal women without known genetic predisposition, high RANKL and progesterone serum levels stratify a subpopulation of women at high risk of developing breast cancer 12-24 months before diagnosis (5.33-fold risk, 95%CI 1.5-25.4; P=0.02). In women with established breast cancer, we demonstrate that RANKL/OPG ratios change dependent on the presence of circulating tumor cells (CTCs). Finally, we show in a prospective human breast cancer cohort that alterations in RANKL/OPG ratios are significantly associated with breast cancer manifestation. These data indicate that the RANKL/RANK/OPG system is deregulated in post-menopausal women at high risk for breast cancer and in women with circulating tumor cells. Thus, serum levels of RANKL/OPG are potentially indicative of predisposition and progression of breast cancer in humans. Advancement of our findings towards clinical application awaits prior validation in independent patient cohorts.
authors.affiliation: Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kiechl
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.|The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schramek
authors.affiliation: Department of Women's Cancer, EGA Institute of Women's Health, University College London, London, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
authors.affiliation: Department of Women's Cancer, EGA Institute of Women's Health, University College London, London, United Kingdom.
authors.forename: Evangelia-Ourania
authors.initials: EO
authors.lastname: Fourkala
authors.affiliation: Department of Women's Cancer, EGA Institute of Women's Health, University College London, London, United Kingdom.|Department of Mathematics, University College London, London, United Kingdom.
authors.forename: Alexey
authors.initials: A
authors.lastname: Zaikin
authors.affiliation: Department of Mathematics, University College London, London, United Kingdom.
authors.forename: Allison
authors.initials: A
authors.lastname: Jones
authors.affiliation: Department of Women's Cancer, EGA Institute of Women's Health, University College London, London, United Kingdom.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Jaeger
authors.affiliation: Department of Women's Cancer, EGA Institute of Women's Health, University College London, London, United Kingdom.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Rack
authors.affiliation: Department of Gynecology and Obstetrics, University Duesseldorf, Duesseldorf, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Janni
authors.affiliation: Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Scholz
authors.affiliation: Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Johann
authors.initials: J
authors.lastname: Willeit
authors.affiliation: Department of Internal Medicine, Bruneck Hospital, Bruneck, Italy.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weger
authors.affiliation: Department of Internal Medicine, Bruneck Hospital, Bruneck, Italy.
authors.forename: Agnes
authors.initials: A
authors.lastname: Mayr
authors.affiliation: Statistical Genomics Group, Paul O'Gorman Building, UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Teschendorff
authors.affiliation: Barts Cancer Institute CR UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Adam
authors.initials: A
authors.lastname: Rosenthal
authors.affiliation: Department of Mathematics, University College London, London, United Kingdom.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Fraser
authors.affiliation: Department of Mathematics, University College London, London, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: Philpott
authors.affiliation: Department of Pathology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Dubeau
authors.affiliation: Department of Surgery, Royal Free and University College London Medical School, London, United Kingdom.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Keshtgar
authors.affiliation: Barts Cancer Institute CR UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Roylance
authors.affiliation: Department of Women's Cancer, EGA Institute of Women's Health, University College London, London, United Kingdom.|UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jacobs
authors.affiliation: Department of Women's Cancer, EGA Institute of Women's Health, University College London, London, United Kingdom.
authors.forename: Usha
authors.initials: U
authors.lastname: Menon
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood / Q000378:metabolism*; D055088:Early Detection of Cancer; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D053244:Osteoprotegerin / Q000097:blood*; D017698:Postmenopause; D011374:Progesterone / Q000097:blood*; D011446:Prospective Studies; D053245:RANK Ligand / Q000097:blood*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000097:blood; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D011374:Progesterone
keywords: Gerotarget; RANKL/RANK; breast cancer