Therapeutic targets for bone metastases in breast cancer

Abstract

Breast cancer is prone to metastasize to bone. Once metastatic cells are in the bone marrow, they do not, on their own, destroy bone. Instead, they alter the functions of bone-resorbing (osteoclasts) and bone-forming cells (osteoblasts), resulting in skeletal complications that cause pathological fractures and pain. In this review, we describe promising molecular bone-targeted therapies that have arisen from recent advances in our understanding of the pathogenesis of breast cancer bone metastases. These therapies target osteoclasts (receptor activator of nuclear factor kB ligand, integrin αvβ3, c-Src, cathepsin K), osteoblasts (dickkopf-1, activin A, endothelin A) and the bone marrow microenvironment (transforming growth factor β, bone morphogenetic proteins, chemokine CXCL-12 and its receptor CXCR4). The clinical exploitation of these bone-targeted agents will provide oncologists with novel therapeutic strategies for the treatment of skeletal lesions in breast cancer.

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.