Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer

// Stefan Kiechl 1 , Daniel Schramek 2,3 , Martin Widschwendter 4 , Evangelia-Ourania Fourkala 4 , Alexey Zaikin 4,5 , Allison Jones 5 , Bernadette Jaeger 4 , Brigitte Rack 4 , Wolfgang Janni 6 , Christoph Scholz 7 , Johann Willeit 1 , Siegfried Weger 8 , Agnes Mayr 8 , Andrew Teschendorff 9 , Adam Rosenthal 10 , Lindsay Fraser 5 , Susan Philpott 5 , Louis Dubeau 11 , Mohammed Keshtgar 12 , Rebecca Roylance 10 , Ian J. Jacobs 4,13 , Usha Menon 4 , Georg Schett 14 and Josef M. Penninger 2 1 Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria 2 IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria 3 The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada 4 Department of Women’s Cancer, EGA Institute of Women’s Health, University College London, London, United Kingdom 5 Department of Mathematics, University College London, London, United Kingdom 6 Department of Gynecology and Obstetrics, University Duesseldorf, Duesseldorf, Germany 7 Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany 8 Department of Internal Medicine, Bruneck Hospital, Bruneck, Italy 9 Statistical Genomics Group, Paul O’Gorman Building, UCL Cancer Institute, University College London, London, United Kingdom 10 Barts Cancer Institute CR UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London, United Kingdom 11 Department of Pathology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA 12 Department of Surgery, Royal Free and University College London Medical School, London, United Kingdom 13 UNSW Australia, Sydney, New South Wales, Australia 14 Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany Correspondence to: Josef M. Penninger, email: // Keywords : breast cancer, RANKL/RANK, Gerotarget Received : October 10, 2016 Accepted : December 05, 2016 Published : December 18, 2016 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.