1. Translating Germline Cancer Risk into Precision Prevention
Matthew B. Yurgelun, Georgia Chenevix-Trench, Scott M. Lippman 
Cell 
Volume 168, Issue 4, Pages (February 2017)
DOI: /j.cell
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2. 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  , DOI: ( /j.cell )
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