Women who carry germline mutations in the tumour suppressor gene BRCA1 have a high lifetime risk of developing basal-like breast cancer, which is thought to arise in an aberrant luminal progenitor population. Ovarian hormones, especially progesterone, are likely to play an important role in the development of BRCA1-associated breast cancer, since prophylactic oophorectomy confers a significant reduction in breast cancer risk in mutation-carriers and deregulated progesterone signaling has been previously observed in BRCA1-mutant breast tissue. Receptor activator of NF-kB ligand (RANKL) is the key paracrine effector of progesterone’s mitogenic action on stem/progenitor cells in the mammary epithelium, and both RANKL and its cognate receptor RANK play a critical role in the development of hormone-driven mammary tumours. Based on these findings, we have investigated a role for this pathway in BRCA1-mutation carriers. We have identified a novel subset of RANK+ luminal progenitors in histologically normal human breast epithelium and in preneoplastic breast tissue from BRCA1 mutation carriers. Notably, RANK+ luminal progenitors isolated from BRCA1-mutant breast tissue were more clonogenic than their RANK– counterparts. Expression profiling revealed RANK+ luminal progenitors are highly mitotically active and bear a molecular signature closely aligned to that of basal-like breast cancer. Importantly, inhibition of RANKL signalling in 3D breast organoid assays using BRCA1-mutant preneoplastic tissue significantly attenuated cellular proliferation, and in vivo prevention studies using BRCA1-deficient mice are currently underway. Our findings suggest that RANKL inhibition may be a promising novel strategy for breast cancer prevention in BRCA1-mutation carriers.