Topic Highlight
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Orthop. Oct 18, 2013; 4(4): 178-185
Published online Oct 18, 2013. doi: 10.5312/wjo.v4.i4.178
Role of RANKL/RANK in primary and secondary breast cancer
Toshiyuki Yoneda, Soichi Tanaka, Kenji Hata
Toshiyuki Yoneda, Division of Hematology and Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
Toshiyuki Yoneda, Soichi Tanaka, Kenji Hata, Department of Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan
Author contributions: Yoneda T directed and designed the study; and Tanaka S and Hata K conducted experiments and produced data.
Correspondence to: Dr. Toshiyuki Yoneda, Division of Hematology and Oncology, Department of Medicine, Indiana University School of Medicine, Walther Hall, R3-C321D, 980 West Walnut Street, Indianapolis, IN 46202, United States.
Telephone: +1-317-2743530 Fax: +1-317-2740396
Received: November 3, 2012
Revised: December 21, 2012
Accepted: January 11, 2013
Published online: October 18, 2013

Bone is one of the most preferential metastatic target sites of breast cancer. Bone possesses unique biological microenvironments in which various growth factors are stored and continuously released through osteoclastic bone resorption, providing fertile soil for circulating breast cancer cells. Bone-disseminated breast cancer cells in turn produce osteotropic cytokines which modulate bone environments. Under the influences of breast cancer-produced cytokines, osteoblasts express elevated levels of Ligand for receptor activator of nuclear factor-κB (RANKL) and stimulate osteoclastogenesis via binding to the receptor receptor activator of nuclear factor-κB (RANK) and activating its downstream signaling pathways in hematopoietic osteoclast precursors, which causes further osteoclastic bone destruction. Establishment of crosstalk with bone microenvironments (so called vicious cycle) is an essential event for metastatic breast cancer cells to develop bone metastasis. RANKL and RANK play a central role in this crosstalk. Moreover, recent studies have demonstrated that RANKL and RANK are involved in tumorigenesis and distant metastasis independent of bone microenvironments. Pharmacological disruption of the RANKL/RANK interplay should be an effective therapeutic intervention for primary breast tumors and bone and non-bone metastasis. In this context, denosumab, which is neutralizing monoclonal antibody against RANKL, is a mechanism-based drug for the treatment of bone metastases and would be beneficial for breast cancer patients with bone metastases and potentially visceral organ metastases.

Keywords: Bone metastasis, Osteoclasts, Bone resorption, Osteoblasts, Stromal cells, Epithelial-mesenchymal transition, Bone pain