Abstract
Many studies have revealed molecular connections between breast and bone. Genes, important in the control of bone remodeling, such as receptor activator of nuclear kappa (RANK), receptor activator of nuclear kappa ligand (RANKL), vitamin D, bone sialoprotein (BSP), osteopontin (OPN), and calcitonin, are expressed in breast cancer and lactating breast. Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) effectors play critical roles during embryonic development, postnatal growth, and epithelial homeostasis, but also are involved in a number of pathological conditions, including wound repair, fibrosis, inflammation, as well as cancer progression and bone metastasis. Transforming growth factor β (TGFβ), insulin-like growth factor I & II (IGF I & II), platelet-derived growth factor (PDGF), parathyroid hormone-related protein (PTH(rP)), vascular endothelial growth factor (VEGF), epithelial growth factors II/I (ErbB/EGF), interleukin 6 (IL-6), IL-8, IL-11, IL-1, integrin αvβ3, matrix metalloproteinases (MMPs), catepsin K, hypoxia, notch, Wnt, bone morphogenetic proteins (BMP), and hedgehog signaling pathways are important EMT and MET effectors identified in the bone microenviroment facilitating bone metastasis formation. Recently, Runx2, an essential transcription factor in the regulation of mesenchymal cell differentiation into the osteoblast lineage and proper bone development, is also well-recognized for its expression in breast cancer cells promoting osteolytic bone metastasis. Understanding the precise mechanisms of EMT and MET in the pathogenesis of breast cancer bone metastasis can inform the direction of therapeutic intervention and possibly prevention.
Highlights
Over 80% of the malignant tumors are of epithelial origin and a number of these carcinomas are highly osteotropic
II/I (ErbB/EGF), interleukin 6 (IL-6), IL-8, IL-11, IL-1, integrin αvβ3, matrix metalloproteinases (MMPs), catepsin K, hypoxia, notch, Wnt, bone morphogenetic proteins (BMP), and hedgehog signaling pathways are important epithelial-to-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) effectors identified in the bone microenviroment facilitating bone metastasis formation
Metastasis is associated with the presence of peripheral blood circulating tumor cells (CTCs) and bone marrow disseminated tumor cells (DTCs) in patients with breast cancer [26,27,28]
Summary
Over 80% of the malignant tumors are of epithelial origin and a number of these carcinomas are highly osteotropic. Bone is the most common site of breast cancer metastasis (70%) [3,4,5,6,7,8,9]. The residual tumors after systemic treatments (hormonotherapy, chemotherapy, or targeted therapy) are enriched for CSCs and have a gene signature with hallmarks of epithelial-mesenchymal transition (EMT)-like properties [19,20,21,22]. Epithelial-mesenchymal transition (EMT) endows metastatic properties upon cancer cells to promote invasion, migration, and subsequent dissemination. The disseminated tumor cells recruited into the target organs may undergo mesenchymal-epithelial transition (MET) that would favor metastasis formation [23,24,25,26]. This article will review the clues and clinical implications of EMT and MET for treatment and possibly prevention of bone metastasis of breast cancer
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