Osteoprotegerin is a potential biomarker of breast cancer risk
The bone metabolism mediators RANK (receptor activator of nuclear factor κB), RANKL (receptor activator of nuclear factor κB ligand) and OPG (osteoprotegerin) have been linked to breast cancer tumorgenesis. The dysregulation of RANK signaling is involved in the pathogenesis of BRCA1 associated breast cancer.
Experimental studies have shown that OPG (the decoy receptor for RANKL) protein levels are significantly lower in BRCA1 mutation carriers, inhibiting RANK signaling. Thus, OPG may serve as a potential biomarker of breast cancer risk.
Learn more: Delineating the role of osteoprotegerin as a marker of breast cancer risk among women with a BRCA1 mutation. Park SS et al., 2022.
Osteoprotegerin a potential biomarker of breast cancer risk
OPG can reliably be measured by ELISA analysis with only 20µl of serum or plasma.
The Biomedica OPG ELISA is the most referenced human OPG ELISA.
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Delineating the role of osteoprotegerin as a marker of breast cancer risk among women with a BRCA1 mutation.
Park SS, Uzelac A, Kotsopoulos J Hered Cancer Clin Pract. 2022 Apr 13;20(1):14. doi: 10.1186/s13053-022-00223-3. PMID: 35418083; PMCID: PMC9008947. Read full publication
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.
Odén L, Akbari M, Zaman T, Singer CF, Sun P, Narod SA, Salmena L, Kotsopoulos J. Oncotarget. 2016. 27;7(52):86687-86694. doi: 10.18632/oncotarget.13417. PMID: 27893411; PMCID: PMC5349945.
Emerging evidence suggests a role of receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) signaling in breast cancer development. Lower osteoprotegerin (OPG) levels, the endogenous decoy receptor for RANKL which competes with RANK for binding of RANKL, has been reported among BRCA mutation carriers. Whether low OPG levels contribute to the high breast cancer risk in this population is unknown. OPG concentrations were measured in plasma of 206 cancer-free BRCA mutation carriers using an enzyme-linked immunosorbent assay. Subjects were categorized as high vs. low based on the median of the entire cohort (95 ng/mL) and followed for a new diagnosis of breast cancer. Cumulative incidence by baseline plasma OPG concentration was estimated using Kaplan-Meier survival analysis. Cox proportional hazards models were used to estimate the adjusted hazard ratios for the association between plasma OPG and breast cancer risk. Over a mean follow-up period of 6.5 years (range 0.1-18.8 years), 18 incident breast cancer cases were observed. After ten years of follow-up, the cumulative incidence of breast cancer among women with low OPG was 21%, compared to 9% among women with high OPG (P-log rank = 0.046). After multivariate adjustment, women with high plasma OPG had a significantly decreased risk of developing breast cancer, compared to women with low OPG (HR = 0.25; 95%CI 0.08-0.78; P = 0.02). These data suggest that low OPG levels are associated with an increased risk of BRCA-associated breast cancer. Targeting RANK signalling may represent a plausible, non-surgical prevention option for BRCA mutation carriers.
Human plasma Osteoprotegerin (OPG) was quantified using the Biomedica OPG ELISA – cat. no. BI-20403 .