Metastasis-the disseminated growth of tumours in distant organs-underlies cancer mortality. Breast-to-brain metastasis (B2BM) is disconcertingly common and disruptive, being prevalent in the aggressive basal-like subtype, albeit evident at varying frequencies in all subtypes. Previous studies revealed parameters of breast cancer metastasis to brain, but its preference for this site remains an enigma. Herein we show that B2BM cells co-opt a neuronal signaling pathway recently implicated in invasive tumour growth, involving activation by glutamate ligand of an N-methyl-Daspartate receptor (NMDAR), whose signaling is demonstrably instrumental in model systems for metastatic colonization of the brain, and associated with poor prognosis. While NMDAR receptor activation is autocrine in some primary tumour types, human and mouse B2BM cells express Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

The epithelial-mesenchymal transition (EMT) plays an important role in breast cancer metastasis, especially in the most aggressive and lethal subtype, "triple-negative breast cancer" (TNBC). Here, we report that CD146 is a unique activator of EMTs and significantly correlates with TNBC. In epithelial breast cancer cells, overexpression of CD146 down-regulated epithelial markers and up-regulated mesenchymal markers, significantly promoted cell migration and invasion, and induced cancer stem cell-like properties. We further found that RhoA pathways positively regulated CD146-induced EMTs via the key EMT transcriptional factor Slug.An orthotopic breast tumor model demonstrated that CD146-overexpressing breast tumors showed a poorly differentiated phenotype and displayed increased tumor invasion and metastasis. We confirmed these findings by conducting an immunohistochemical analysis of 505 human primary breast tumor tissues and found that CD146 expression was significantly associated with high tumor stage, poor prognosis, and TNBC. CD146 was expressed at abnormally high levels (68.9%), and was strongly associated with E-cadherin down-regulation in TNBC samples. Taken together, these findings provide unique evidence that CD146 promotes breast cancer progression by induction of EMTs via the activation of RhoA and up-regulation of Slug. Thus, CD146 could be a therapeutic target for breast cancer, especially for TNBC.biomarker | F-actin B reast cancer is the most common malignancy and the leading cause of cancer mortality in women worldwide (1). Death from breast cancer primarily results from cancer cells invading surrounding tissues and metastasizing to distal organs followed by formation of secondary tumors (1). The epithelial to mesenchymal transition (EMT), a developmental process in which epithelial cells lose polarity and develop a mesenchymal phenotype, has been implicated in the initiation of metastasis (2).It is believed that EMTs endow cancer cells with migratory and invasive properties, and induce cancer stem cell (CSC) properties (2, 3). The primary events of an EMT are the loss of epithelial markers, followed by increased expression of mesenchymal markers, and rearrangement of the cytoskeleton. Previous reports reveal that EMTs can be regulated by several transcription factors, including SIP1, Snail, Slug, and Twist, which inhibit the epithelial phenotype and repress E-cadherin transcription (2, 4). A number of signal pathways converge on these transcription factors to induce an EMT, including the activation of small GTPases, especially RhoA, which regulates actin cytoskeleton reorganization (5). Increasing evidences show that in breast cancer, malignant cells undergo an EMT to become motile, especially in the most lethal and aggressive subtype, ER− triple-negative breast cancer (TNBC) (6). CD146, also known as MCAM, M-CAM, and MUC18, was first identified as a melanoma-specific cell-adhesion molecule (7). Our previous findings have showed that CD146 is a marker for tumor angiogenesis (8), and that CD146 is...

CD146 is a novel endothelial biomarker and plays an essential role in angiogenesis; however, its role in the molecular mechanism underlying angiogenesis remains poorly understood. In the present study, we show that CD146 interacts directly with VEGFR-2 on endothelial cells and at the molecular level and identify the structural basis of CD146 binding to VEGFR-2. In addition, we show that CD146 is required in VEGF-induced VEGFR-2 phosphorylation, AKT/p38 MAPKs/NF-κB activation, and thus promotion of endothelial cell migration and microvascular formation. Furthermore, we show that anti-CD146 AA98 or CD146 siRNA abrogates all VEGFR-2 activation induced by VEGF. An in vivo angiogenesis assay showed that VEGF-promoted microvascular formation was impaired in the endothelial conditional knockout of CD146 (CD146(EC-KO)). Our animal experiments demonstrated that anti-CD146 (AA98) and anti-VEGF (bevacizumab) have an additive inhibitory effect on xenografted human pancreatic and melanoma tumors. The results of the present study suggest that CD146 is a new coreceptor for VEGFR-2 and is therefore a promising target for blocking tumor-related angiogenesis.