Abstract S2-04: RANK ligand as a target for breast cancer prevention inBRCA1mutation carriers

Abstract Background: BRCA1 mutation carriers commonly undergo prophylactic mastectomy to reduce their risk of breast cancer. The precise role of chemoprevention with tamoxifen, which reduces the incidence of ER-positive breast cancer in the general population, is uncertain for BRCA1 mutation carriers, where uptake has been modest. The identification of an effective and acceptable prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1mut/+ tissue harbors an aberrant population of luminal progenitor cells and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Since Receptor Activator of Nuclear Factor-kappa B ligand (RANKL) is a key paracrine effector of progesterone signaling, and RANKL and its receptor RANK contribute to mammary tumorigenesis, we investigated a role for this pathway in the preneoplastic phase of BRCA1 mutation carriers. Methods: We explored a role for the RANK/RANKL pathway during the preneoplastic phase in freshly isolated (histologically normal) patient specimens from BRCA1 mutation carriers using several approaches. RANK and RANKL expression in breast cancer was evaluated in formalin fixed paraffin embedded (FFPE) archival sections by IHC from the kConFab and the Amgen Tissue Banks. All samples were obtained with patient consent and relevant IRB approval. A role for RANKL inhibition in attenuating tumor onset was studied using the MMTV-cre/Brca1fl/fl/p53+/– mouse model that recapitulates human basal-like breast cancer. Results: We identified two subsets of luminal progenitors (RANK+ and RANK–) in histologically normal tissue of BRCA1 mutation carriers and found that RANK+ cells are highly proliferative, exhibit grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. Moreover, high levels of RANK expression prevailed in established BRCA1-associated tumors. These data suggest that RANK+ and not RANK– progenitors are a key target population in these women. Notably, inhibition of RANKL signaling by denosumab in 3D breast organoids derived from pre-neoplastic BRCA1mut/+ tissue attenuated progesterone-induced proliferation. Furthermore, inhibition of RANKL with either the RANKL inhibitor OPG-Fc or a RANKL monoclonal antibody in a Brca1-deficient mouse model significantly curtailed mammary tumorigenesis, when compared to controls (p<0.001). Conclusions: Together these findings identify a targetable pathway in a putative cell of origin population in BRCA1 mutation carriers and implicate RANKL blockade as a promising breast cancer prevention strategy. Citation Format: Lindeman GJ, Nolan E, Vaillant F, Branstetter D, Pal B, Giner G, Whitehead L, Lok SW, Mann GB, kConFab Consortium, Rohrbach K, Huang L-Y, Soriano R, Smyth GK, Dougall WC, Visvader JE. RANK ligand as a target for breast cancer prevention in BRCA1 mutation carriers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-04.