Figure 1

In bone, breast cancer cells secrete different factors that stimulate osteoclast differentiation and maturation through the activation of the RANKL/RANK or the Jagged1/Notch signaling pathways. Then, integrin, Src and cathepsin K play an essential role in the bone-resorbing activity of mature osteoclasts. In addition, breast cancer cells secrete components (DKK-1, activin A) that inhibit osteoblast differentiation. This leads to enhanced bone destruction and, as a consequence, to the release of bone derived-factors (TGF-β) that stimulate tumor growth. Moreover, CXCL-12 produced by osteoblasts promotes the recruitment and survival of CXCR4-expressing breast cancer cells. There is therefore a 'vicious cycle' (depicted by the large blue arrows) whereby metastatic cells stimulate osteoclast-mediated bone resorption and growth factors released from resorbed bone stimulate tumor growth. Red boxes highlight components that are attractive therapeutic targets, some of which are in clinical development. The drawings were produced using Servier Medical Art [55]. Abbreviations: CXCL-12, C-X-C motif chemokine 12; CXCR4, C-X-C chemokine receptor type 4; DKK-1, dickkopf-1; FPPS, farnesyl pyrophosphate synthase; IL, interleukin; M-CSF, macrophage-colony stimulating factor; PGE2, prostaglandin E2; PTHrP, parathyroid hormone-related peptide; RANK, receptor activator of nuclear factor kB; RANKL, RANK ligand; Src, proto-oncogene tyrosine-protein kinase; TGF-β, transforming growth factor-β.