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

AbstractWomen with a pathogenic germline mutation in theBRCA1 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 theBRCA1 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) sign aling in the pathogenesis ofBRCA1-associated breast cancer. Experimental studies have demonstrated that RANK inhibition suppressesBrca1-mammary tumorigenesis, suggesting a potential target for prevention. Data from studies conducted among women with aBRCA1 mutation further support this pathway inBRCA1-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 aBRCA1 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 ...
Source: Hereditary Cancer in Clinical Practice - Category: Cancer & Oncology Source Type: research