Translating Germline Cancer Risk into Precision Prevention Matthew B. Yurgelun, Georgia Chenevix-Trench, Scott M. Lippman  Cell  Volume 168, Issue 4, Pages 566-570 (February 2017) DOI: 10.1016/j.cell.2017.01.031 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 RANK-L Blockade as a Prevention Strategy A series of studies (e.g., in Brca1-deficient mice and BRCA1-mutant organoids) suggest the following schema: BRCA1mut/+ RANK+ subset of mammary luminal progenitor (LP) cells (left) give rise to basal-like tumors (far right). Progesterone-dependent RANK signaling in LP cells is responsive to RANK-L inhibition. Subsequent NF-κB-activated (involving DNA damage [ATM]), progesterone-independent cells may be less sensitive to RANK-L inhibition and more sensitive to IKKα and PARP inhibitor prevention. Denosumab (human monoclonal antibody [red] targeting RANK-L [pink]) could abrogate progesterone-dependent, mitogenic signaling of RANK+ BRCA1mut/+ LP cells to prevent basal-like tumors. Given these and other compelling data (see text), an international breast cancer prevention trial of denosumab is planned for BRCA1-mutation carriers (bottom). Abbreviations are as follows: RANK, receptor activator of nuclear factor kappa-B (NF-kB); RANK-L, RANK ligand; ER, estrogen receptor; PR, progesterone receptor; MaSC, mammary stem cell; NEMO, NF-κB essential modulator; ATM, ataxia telangiectasia mutated; IKKα, inhibitor of kappaB kinase alpha; PARP, poly (ADP-ribose) polymerase. Cell 2017 168, 566-570DOI: (10.1016/j.cell.2017.01.031) Copyright © 2017 Elsevier Inc. Terms and Conditions