RANKL/OPG in Breast Cancer — Extending Its Territory to BRCA Mutation Carriers

Receptor activator of nuclear factor-ĸB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG) are established as essential determinants of bone health and a dysregulation of this system towards RANKL results in osteoporosis (Rachner et al., 2011). Based on these findings, denosumab, a monoclonal antibody directed against RANKL was developed and has now been approved for the treatment of osteoporosis and bone metastases (Rachner et al., 2011). In the past years, an additional role of the RANKL/OPG system in mammary carcinogenesis has been recognized. Until now, most studies addressing this topic have focused on the role of RANKL as the direct effector molecule in this system. Two simultaneously published studies in 2010 convincingly provided evidence to show that RANKL mediates progestin-driven mammary carcinogenesis (Schramek et al., 2010; Gonzalez-Suarez et al., 2010). Upon exposure of mice to progesterone or progesterone derivatives the local expression of RANKL is highly increased in mammary cells. Increased carcinogenesis observed in the presence of medroxyprogesterone and the carcinogen 7,12dimethylbenz(a)anthracene (DMBA) is prevented by both the genetic inhibition of RANK, which acts as the receptor for RANKL (Schramek et al., 2010) or by pharmacological inhibition of RANKL (GonzalezSuarez et al., 2010). In addition, tumour-infiltrating regulatory T cells have been shown to promote metastases by producing high levels of RANKL (Tan et al., 2011). In this issue of EBioMedicine, Widschwendter and colleagues extend the scope of the RANKL/OPG system to women with BRCA-mutations (Widschwendter et al., 2015). BRCA-mutations occur infrequently and account for about 5 to 10% of all breast cancers and 15% of ovarian