CD146, an epithelial-mesenchymal transition inducer, is associated with triple-negative breast cancer

Abstract

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...

Surface markers distinguishing mesenchymal stem cells from fibroblasts

“…It was shown that CD106 protein was expressed only on MSCs but not on fibroblasts (10). CD146 (also known as melanoma cell adhesion molecule MCAM) is important for endothelial cell migration and angiogenesis (15). It was shown that only 4.83% of fibroblasts were CD146 positive compared with MSCs of early (91.7%) and late (79.8%) passages (10).…”

Targeting CD146 with a 64 Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas

“…recently, induction of epithelial-mesenchymal transition (EMT), has also been documented (7,8). Despite the copious body of data describing the expression of CD146 in a myriad of cancers, noninvasive in vivo molecular imaging of CD146 expression has remained unexplored.…”

Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension

“…CD146 was first identified as a marker for melanoma progression 13 . Later on, CD146 was also identified as a factor in angiogenesis, and tumour cell invasion and migration [14][15][16][17] . We have previously reported that CD146 regulates cell migration through cytoskeleton proteins by activating the small GTPase RhoA 18 .…”

“…These results strongly suggest that CD146 is a negative regulator of canonical Wnt signalling at the b-catenin level. Although CD146 has been extensively studied in tumour metastasis, invasion and angiogenesis, its ligand is still under investigation 16,[32][33][34] . As a non-canonical Wnt ligand, Wnt5a has a critical role in regulating cell motility, cell polarity and CE during embryo gastrulation.…”

“…S17), implying the involvement of CD146 in colon cancer. We have previously reported that CD146 induces the epithelial-mesenchymal transition by downregulating the expression of E-cadherin in breast cancer cell lines 16 . E-cadherin, an adhesion molecule anchoring b-catenin to the cell membrane, has been identified as a canonical Wnt target gene and is positively regulated by Wnt 41,42 .…”