RANK, RANKL and OPG Expression in Breast Cancer – Influence on Osseous Metastasis

Abstract

!In women, malignant breast tumours are among the most common malignant diseases in Europe. In advanced breast cancer, the risk of bone metastasis increases to 65-75 %. The discovery of the physiological bone metabolism parameters RANK (receptor activator of nuclear factor-κB), RANKL (receptor activator of nuclear factor-κB ligand) and OPG (osteoprotegerin) as well as their pathophysiological involvement in bone-related diseases is the subject of new therapeutic strategies. The formation of osteolytic bone metastasis requires increased osteoclast activity. Activation of osteoclasts by excessive direct RANKL or reduced OPG expression of osseous metastatic tumour cells remains to be elucidated. More than 50 % of primary breast cancer cells express OPG and RANK, while RANKL could be detected only in 14-60 %. Increased OPG concentrations in the serum of patients with bone metastases have been shown in several studies, whereas the RANKL results are described in an opposite manner. The use of OPG as a biomarker for the detection of osteolytic bone metastases is not consistent and needs to be proved in further studies. Increased RANKL activity was found in diseases characterised by excessive bone loss and formed the basis of new therapeutic options. In several studies, a human monoclonal antibody to RANKL (denosumab) was investigated for the treatment of bone diseases. Denosumab is a promising therapeutic option due to its bone-protective effects. Zusammenfassung

Osteoprotegerin rich tumor microenvironment: implications in breast cancer

“…These factors are known to increase the breast cancer development by regulating patient survival, bypassing apoptosis, invasion, migration and tumor angiogenesis [24]. OPG, TRAIL, and RANKL are significantly higher in tumor epithelial cells from patients with breast cancer than in epithelial cells of non-neoplastic breast tissues [25]. Moreover, the expression of OPG, TRAIL, RANKL, and RANK was significantly higher in spindle-shaped stromal cells from patients with breast cancer than in non-neoplastic tissue stromal cells [25].…”

“…Patients with estrogen receptor-positive (ER+) breast cancer constitute a major clinical population who are at risk for bone metastases [26]. More than 50% of primary breast cancer cells express OPG and RANK, while RANKL could be detected only in 14-60% [25]. OPG is one of the important players of the OPG/ receptor activator of nuclear factor kappa-B (RANK)/RANK ligand (RANKL) triad (Figure 2), and is a secreted member of the TNFR superfamily of proteins [27].…”

MicroRNA-34a alleviates steroid-induced avascular necrosis of femoral head by targeting Tgif2 through OPG/RANK/RANKL signaling pathway

“…Discovery of physiological bone metabolism parameters such as Receptor Activator of Nuclear factor Kappa B (RANK), Receptor Activator of Nuclear factor Kappa Ligand (RANKL) and Osteoprotegerin (OPG) and studies on physiologicaland pathological mechanisms of those provide new targets for the treatment of SANFH. 5,6 MiR-34a can inhibit tumor by participating in proliferation, migration and metastasis of tumor cells. In addition, evidence showed that miR-34a can suppress invasion and metastasis by directly regulating Tgif2 in gastric cancer.…”

Polymorphisms in the RANK/RANKL genes and their effect on bone specific prognosis in breast cancer patients

“…Looking at these separate analyses, the effect on prognosis was only seen with regard to bone metastasisfree survival. Concerning the hypothesis that genetic variants of the RANK/RANKL/OPG system might act through an effect of the skeleton, this result underlines the hypothesis of the RANK pathway being associated specifically with osseous metastases [43].…”