The Roles of Epithelial-to-Mesenchymal Transition (EMT) and Mesenchymal-to-Epithelial Transition (MET) in Breast Cancer Bone Metastasis: Potential Targets for Prevention and Treatment

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.

Rhodiola crenulata inhibits Wnt/β-catenin signaling in glioblastoma

“…Changes observed in EMT markers such as increased E-cadherin and decreased Vimentin expression further suggest changes noted are secondary to differentiation. As previously described functional loss or downregulation of E-cadherin from epithelial cells is a hallmark of EMT [22]. GFAP is a protein largely found in astrocytes and a protein marker of differentiation.…”

S100B expression in breast cancer as a predictive marker for cancer metastasis

“…Metastasis-related pathways, such as the transition between the epithelial and mesenchymal phenotype, were altered by inflammatory molecules (29). Tumor cells secrete interleukin (IL)-6 and IL-8, which are important mediators of EMT in breast cancer (30). In addition, tumor cells secrete IL-6 and IL-8, which affect the phenotypes in an autocrine manner and IL-8 promotes the mesenchymal phenotype (31,32).…”

OPN-a Splicing Variant Expression in Non-small Cell Lung Cancer and its Effects on the Bone Metastatic Abilities of Lung Cancer Cells In Vitro

“…It has been suggested that OPN and αvβ3 integrin interaction may mediate many of the activities necessary for this initial step in the bone metastasis of malignancies. A number of studies showed that overexpression of OPN were determinative of a high incidence of bone metastases in breast cancer (25). Likewise, in prostate cancer, activation of αvβ3 integrin allows cancer cells to adhere and migrate to bone matrix at early stages of skeletal metastasis (26).…”