title: RANKL/RANK: from bone loss to the prevention of breast cancer.
abstract: RANK and RANKL, a receptor ligand pair belonging to the tumour necrosis factor family, are the critical regulators of osteoclast development and bone metabolism. Besides their essential function in bone, RANK and RANKL have also been identified as the key factors for the formation of a lactating mammary gland in pregnancy. Mechanistically, RANK and RANKL link the sex hormone progesterone with stem cell expansion and proliferation of mammary epithelial cells. Based on their normal physiology, RANKL/RANK control the onset of hormone-induced breast cancer through the expansion of mammary progenitor cells. Recently, we and others were able to show that RANK and RANKL are also critical regulators of BRCA1-mutation-driven breast cancer. Currently, the preventive strategy for BRCA1-mutation carriers includes preventive mastectomy, associated with wide-ranging risks and psychosocial effects. The search for an alternative non-invasive prevention strategy is therefore of paramount importance. As our work strongly implicates RANK and RANKL as key molecules involved in the initiation of BRCA1-associated breast cancer, we propose that anti-RANKL therapy could be a feasible preventive strategy for women carrying BRCA1 mutations, and by extension to other women with high risk of breast cancer.
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr Bohrgasse 3, 1030 Vienna, Austria.
authors.forename: Verena
authors.identifier: 0000-0002-5565-8198
authors.initials: V
authors.lastname: Sigl
authors.affiliation: School of Medicine, Department of Pharmacology, University of Maryland, Baltimore, MD 21201, USA.
authors.forename: Laundette P
authors.initials: LP
authors.lastname: Jones
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr Bohrgasse 3, 1030 Vienna, Austria josef.penninger@imba.oeaw.ac.at.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002986:Clinical Trials as Topic; D000069448:Denosumab / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008408:Mastectomy; D009154:Mutation; D010024:Osteoporosis / Q000378:metabolism*; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D000069448:Denosumab
keywords: BRCA1; RANK/RANKL; breast cancer