Abstract
PurposeEmerging evidence suggests that the progesterone-mediated receptor activator of nuclear factor κB (RANK)/soluble RANK ligand (sRANKL)/osteoprotegerin (OPG) pathway plays an important role in mammary carcinogenesis and is hyperactivated in germline (g)BRCA1/2 mutation carriers. We analyzed the effects of a 3-month intensive lifestyle intervention within the LIBRE-1 study on the serum levels of OPG and sRANKL and hypothesized that the intervention program provides a beneficial impact on the biomarkers by increasing OPG and reducing sRANKL serum concentrations.MethodsSerum levels of OPG and sRANKL of 49 gBRCA1/2 mutation carriers were quantified using enzyme-linked immunosorbent assays. We used previously collected blood samples from participants of the prospective LIBRE-1 study, who were randomized into an intervention group (IG), increasing physical activity and adherence to the Mediterranean diet (MedD) through supervised sessions from study entry to the first study visit after 3 months and a usual-care control group (CG). Differences in biomarker levels before and after the 3-month intervention were tested within and between study groups.ResultsThe lifestyle intervention resulted in a significant increase in OPG for participants in both the IG (q = 0.022) and CG (q = 0.002). sRANKL decreased significantly in the IG (q = 0.0464) and seemed to decrease in the CG (q = 0.5584). An increase in the intake of Omega-3 polyunsaturated fatty acids was significantly associated with an increase in OPG (r = 0.579, q = 0.045). Baseline serum levels of sRANKL were a strong predictor for the change of sRANKL in the course of the intervention (ß-estimate = − 0.70; q = 0.0018). Baseline physical fitness (assessed as VO2peak) might predict the change of OPG in the course of the intervention program (ß-estimate = 0.133 pg/ml/ml/min/kg; p = 0.0319; q = 0.2871).ConclusionFindings from this pilot study seem to confirm our hypothesis by showing an increase in OPG and decrease in sRANKL over a 3-month lifestyle intervention and suggest that increased physical activity and adherence to the MedD are potent modulators of the biomarkers OPG and potentially sRANKL.
Highlights
Women with a germline mutation in the tumor suppressor genes BRCA1/2 have a high lifetime risk of developing breast cancer (BC) or ovarian cancer (OC) (69–72% and 16–59%, respectively) [1]
To test whether our subgroup of 49 individuals differed from the total LIBRE-1 cohort (n = 68) in any of the characteristics shown in Table 1, we performed Mann–Whitney U tests between these cohorts, which showed no statistically significant results
The intervention group (IG) showed a significant decrease in soluble RANK ligand (sRANKL), while the decrease in this biomarker was nonsignificant for the control group (CG) (Table 2, Fig. 2B)
Summary
Women with a germline mutation in the tumor suppressor genes BRCA1/2 have a high lifetime risk of developing breast cancer (BC) or ovarian cancer (OC) (69–72% and 16–59%, respectively) [1]. With regards to the potential of chemoprevention, current findings suggest that the osteoprotegerin (OPG)/receptor activator of nuclear factor (NF)-κB (RANK)/ RANK ligand (RANKL) pathway, a key regulator in bone metabolism, plays a crucial role in the tumorigenesis of gBRCA1/2associated BC [8,9,10,11,12,13]. The activation of the NF-κB pathway through progesterone-dependent RANK/RANKL signaling leads to breast tissue proliferation [14,15,16], as well as the induction of BC [17, 18], while genetic and pharmacological RANK inhibition reduce the likelihood of tumor formation [13]. Functioning as a decoy receptor for RANKL, lower OPG levels lead to a weaker RANKL inhibition, resulting in up to 75% higher BC risk for gBRCA1 mutation carriers with below-average OPG levels compared to high-risk patients with above-average serum levels [26]
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