Out-RANKing BRCA1 in Mutation Carriers.

Beyond prophylactic mastectomy, there are currently very few options available to BRCA1 mutation carriers to help reduce their risk of developing breast cancer. An effective prevention therapy therefore remains a pressing area of need. Accumulating evidence points to amplification of the progesterone signaling axis in precancerous tissue from BRCA1 mutation carriers. Given that RANKL is an important paracrine mediator of hormonal signaling in breast tissue, there has been considerable interest in exploring a potential role for this pathway in oncogenesis. Recent findings indicate that the RANK and NF-κB pathways are aberrantly activated in luminal progenitor cells resident in preneoplastic BRCA1mut/+ breast tissue. The augmented proliferation of these cells and their predilection for DNA damage suggest that they are prime cellular targets for basal-like cancers arising in BRCA1 mutation carriers. The end result is a hyperactive pathway, initiated by progesterone and amplified by DNA damage-induced NF-κB signaling, that likely accounts for the susceptibility of BRCA1mut/+ luminal progenitor cells to oncogenesis and tissue specificity. Specific targeting of this progenitor subset has revealed a compelling new prevention strategy for these and possibly other high-risk women. Cancer Res; 77(3); 595-600. ©2017 AACR.