Figure 1

Breast cancer-bone interactions in skeletal metastasis using the receptor activator of NF-κB ligand (RANKL)/RANK pathway. Expression of RANK enables breast cancer cells to migrate to bone where the cognate ligand RANKL is abundantly expressed by osteoblasts. Some tumour cells express RANKL, whereas others further enhance RANKL expression by cell-to-cell contact of tumour cells with osteoblastic lineage cells. This enables breast cancer cells to enter a vicious circle where they stimulate bone-destroying osteoclasts that express RANK (first loop). Bone degradation by osteoclasts creates further space for expansive tumour growth within the bone microenvironment and releases a variety of growth factors and cytokines that have been deposited by osteoblasts, including parathyroid hormone-related peptide (PTHrP), IL-6, and transforming-growth factor (TGF)-β, and that serve as tumour survival factors (second loop). OAF, osteoclast activating factor.