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

作者：Kiechl Stefan; Schramek Daniel; Widschwendter Martin; Fourkala Evangelia Ourania; Zaikin Alexey; Jones Allison; Jaeger Bernadette; Rack Brigitte; Janni Wolfgang; Scholz Christoph; Willeit Johann; Weger Siegfried; Mayr Agnes; Teschendorff Andrew; Rosenthal Adam; Fraser Lindsay; Philpott Susan; Dubeau Louis; Keshtgar Mohammed; Roylance Rebecca; Jacobs Ian J; Menon Usha; Schett Georg; Penninger Josef M^*

来源：Oncotarget, 2017, 8(3): 3811-3825.

DOI：10.18632/oncotarget.14013

• breast cancer
• RANKL/RANK
• Gerotarget

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.

• 出版日期2017-1-17