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

• DOI: 10.18632/oncotarget.14013
• Publication Date: 2016-12-19T14:19:58Z
• Authors: Stefan Kiechl; Daniel Schramek; Martin Widschwendter; Evangelia-Ourania...; Alexey Zaikin; Allison Jones; Bernadette Jaeger; Brigitte Rack; Wolfgang Janni; Christoph Scholz; Johann Willeit; Siegfried Weger; Agnes Mayr; Andrew Teschendorff; Adam Rosenthal; Lindsay Fraser; Susan Philpott; Louis Dubeau; Mohammed Keshtgar; Rebecca Roylance; Ian J. Jacobs; Usha Menon; Georg Schett; Josef M. Penninger
• Keywords: 0301 basic medicine; Receptor Activator of Nuclear Factor-kappa B; Gerotarget; RANK Ligand; Osteoprotegerin; Breast Neoplasms; Neoplastic Cells, Circulating; Up-Regulation; 3. Good health; Gene Expression Regulation, Neoplastic; Postmenopause; 03 medical and health sciences; breast cancer; Biomarkers, Tumor; Humans; RANKL/RANK; Female; Prospective Studies; Early Detection of Cancer; Progesterone; Research Paper

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.