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Abstract
Breast cancer remains one of the most life-threatening tumors affecting women. Most patients with advanced breast cancer eventually develop metastatic diseases, which cause significant morbidity and mortality. Approximately two-thirds of patients with advanced breast cancer exhibit osteolytic-type bone metastasis, which seriously reduce the quality of life. Therefore, development of novel therapeutic strategies for treating breast cancer patients with bone metastasis is urgently required. The “seed and soil” theory, which describes the interaction between the circulating breast cancer cells (seeds) and bone microenvironment (soil), is widely accepted as the mechanism underlying metastasis. Disruption of any step in this cycle might have promising anti-metastasis implications. The interaction of receptor activator of nuclear factor-κB ligand (RANKL) and its receptor RANK is fundamental in this vicious cycle and has been shown to be a novel effective therapeutic target. A series of therapeutic strategies have been developed to intervene in this cross-talk. Therefore, in this review, we have systematically introduced the functions of the RANKL/RANK signaling system in breast cancer and discussed related therapeutic strategies.
Highlights
Breast cancer is one of the most common cancers and the leading cause of mortality in females
Canon et al showed that administration of an OPG-Fc construct in a mouse model with breast cancer bone metastasis may block skeletal tumor progression and improve survival by inhibiting Receptor activator of nuclear factor-κB ligand (RANKL) (Canon et al, 2008)
The common cause of death for breast cancer patients is bone metastasis, nearly 80% of which are due to osteolytic lesions
Summary
Breast cancer is one of the most common cancers and the leading cause of mortality in females. In addition to the rich microenvironment of the bone tissue, the abundantly secreted RANKL can attract RANK-expressing circulating breast cancer cells to migrate into bone matrix, apart from the C-X-C chemokine receptor type (CXCR) 4/12 interaction. In the case of osteolytic metastases, circulating breast cancer cells highly enhance osteoclast activities, and seriously inhibit osteoblast differentiation and result in increased bone resorption and decreased bone formation, leading to higher risk of fractures. They demonstrated that the osteoblasts and bone marrow stromal cells that produced RANKL could attract RANK-expressing tumor cells, and induce their migration This mechanism is widely accepted and has been observed in many other types of cancer, including breast cancer. Study of Denosumab as Adjuvant Treatment for Women with High Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE)
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