More importantly, the expression levels of CTGF and RANKL showed a strong positive correlation in human primary breast tumor tissues and were higher in bone metastases than in other site metastases.
Additionally, overexpression of receptor activator of nuclear factor κB ligand (RANKL) in the bone microenvironment drives the vicious, destructive cycle of progression of bone metastasis and bone resorption.
Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer.
AS2676293 suppressed RANKL-mediated tumour migration in the transwell assay and inhibited bone metastasis of the murine cell line B16F10, which is known not to trigger osteoclast activation.
While receptor activator of NF-κB ligand (RANKL) targeting therapy may not affect the induction of CSCs, RANKL is a potential target for prevention as well as treatment of breast cancer bone metastasis.
Denosumab is a monoclonal RANKL antibody, which was originally introduced for the treatment of osteoporosis and bone metastases from solid tumors, but more recently has been used for treatment of giant cell tumor of bone (GCTB).
Matrix metalloproteinases (MMPs), receptor activator of nuclear factor‑κB ligand (RANKL) and runt‑related transcription factor 2 (RUNX2), which are involved in cell growth and bone metastasis, are frequently activated or overexpressed in various types of cancer, including PCa.
It is abundantly clear that tumor-derived parathyroid hormone-related protein (PTHrP), receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) are central contributors in promoting osteolytic process of breast carcinoma bone metastasis.
Denosumab, an antibody targeting RANKL, is used to treat osteoporosis and to prevent skeletal related events (SREs) in patients with bone metastases originating from solid tumors.
The receptor activator of nuclear factor κ B ligand (RANKL) inhibitor denosumab and bisphosphonates (e.g. zoledronic acid) are approved in Europe for the prevention of skeletal-related events (pathologic fracture, radiation or surgery to bone, and spinal cord compression) in adults with bone metastases secondary to solid tumours.
RANKL is able to induce the expression of proteolytic enzymes, well-known markers of osteoclastogenesis, triggering a vicious cycle in osteolytic bone metastasis.
MDA-MB-231 breast cancer cells and mouse osteoblast MC3T3-E1 cells were cocultured to mimic the breast cancer bone metastasis microenvironment <i>in vitro</i>. qRT-PCR and Western blotting were used to detect the expressions of OPG and RANKL at the mRNA and protein levels, respectively, in brucine-treated cultures and they were compared to those in untreated cultures.
Low RANKL mRNA expression in early breast cancer patients is of prognostic significance for increased risk for relapse and bone metastases and might potentially guide clinical decision-making for the use of anti-RANKL agents in the treatment of early breast cancer patients at high risk for metastatic spread, provided that our findings are validated in independent cohorts.
Thousands of cancer patients worldwide are already taking RANKL inhibitors for the management of bone metastasis, given the relevance of this pathway in osteoclastogenesis and bone resorption.
Bone homeostasis critically relies on the RANKL-RANK-OPG axis which can be targeted by the fully human monoclonal antibody denosumab in conditions with increased bone resporption such as bone metastases.
Although the mechanisms of the development of BM are not completely clear, it is now well understood that the Receptor Activator of Nuclear factor Kappa-B-/Ligand (RANK/RANKL)/osteoprotegerin (OPG) pathway plays a relevant role.
Gene expression analysis from bone metastases at day 55 revealed that tumor-produced integrins (αvβ5) as well as factors relevant for angiogenesis (αvβ3, VEGF, PDGF), bone resorption (PTHrP and RANKL), extracellular matrix remodeling (collagen, CD44) and bone marrow microenvironment (CXCR4) were significantly reduced upon therapy with cilengitide.