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Women with a pathogenic germline mutation in the  BRCA1  gene face a very high lifetime risk of developing breast cancer, estimated at 72% by age 80. Prophylactic bilateral mastectomy is the only effective way to lower their risk; however, most women with a mutation opt for intensive screening with annual MRI and mammography. Given that the  BRCA1  gene was identified over 20 years ago, there is a need to identify a novel non-surgical approach to hereditary breast cancer prevention. Here, we provide a review of the emerging preclinical and epidemiologic evidence implicating the dysregulation of progesterone-mediated receptor activator of nuclear factor κB (RANK) signaling in the pathogenesis of  BRCA1 -associated breast cancer. Experimental studies have demonstrated that RANK inhibition suppresses  Brca1- mammary tumorigenesis, suggesting a potential target for prevention. Data from studies conducted among women with a  BRCA1  mutation further support this pathway in  BRCA1 -associated breast cancer development. Progesterone-containing (but not estrogen-alone) hormone replacement therapy is associated with an increased risk of breast cancer in women with a  BRCA1  mutation. Furthermore,  BRCA1  mutation carriers have significantly lower levels of circulating osteoprotegerin (OPG), the decoy receptor for RANK-ligand (RANKL) and thus endogenous inhibitor of RANK signaling. OPG levels may be associated with the risk of disease, suggesting a role of this protein as a potential biomarker of breast cancer risk. This may improve upon current risk prediction models, stratifying women at the highest risk of developing the disease, and further identify those who may be targets for anti-RANKL chemoprevention. Collectively, the evidence supports therapeutic inhibition of the RANK pathway for the primary prevention of  BRCA1 -associated breast cancer, which may generate unique prevention strategies (without prophylactic surgery) and enhance quality of life.

Delineating the role of osteoprotegerin as a marker of breast cancer risk among women with a BRCA1 mutation