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Abstract
Epithelial-mesenchymal transition (EMT) is one of the decisive steps regulating cancer invasion and metastasis. However, the molecular mechanisms underlying this transition require further clarification. MDA-9/syntenin (SDCBP) expression is elevated in breast cancer patient samples as well as cultured breast cancer cells. Silencing expression of MDA-9 in mesenchymal metastatic breast cancer cells triggered a change in cell morphology in both 2D- and 3D-cultures to a more epithelial-like phenotype, along with changes in EMT markers, cytoskeletal rearrangement and decreased invasion. Conversely, over expressing MDA-9 in epithelial non-metastatic breast cancer cells instigated a change in morphology to a more mesenchymal phenotype with corresponding changes in EMT markers, cytoskeletal rearrangement and an increase in invasion. We also found that MDA-9 upregulated active levels of known modulators of EMT, the small GTPases RhoA and Cdc42, via TGFβ1. Reintroducing TGFβ1 in MDA-9 silenced cells restored active RhoA and cdc42 levels, modulated cytoskeletal rearrangement and increased invasion. We further determined that MDA-9 interacts with TGFβ1 via its PDZ1 domain. Finally, in vivo studies demonstrated that silencing the expression of MDA-9 resulted in decreased lung metastasis and TGFβ1 re-expression partially restored lung metastases. Our findings provide evidence for the relevance of MDA-9 in mediating EMT in breast cancer and support the potential of MDA-9 as a therapeutic target against metastatic disease.
Highlights
The American Cancer Society estimates that in 2016, about 246,660 women will be diagnosed with breast cancer and approximately 40,450 women will die of the disease in the United States (American Cancer Society, Cancer Facts & Figures, 2016)
Breast tumor tissue and metastatic lesions showed an increased expression of MDA-9 as compared to normal breast tissue (Figure 1a). This finding is in agreement with previous studies and was performed to verify previously published research to confirm that MDA-9/syntenin expression was elevated in breast cancer tissues and metastatic breast cancer cell lines [13, 19, 20]
We assessed the expression of MDA-9 in a number of non-metastatic and metastatic human breast cancer cell lines and found that MDA-9 expression was elevated in metastatic cells at both the protein (Figure 1b) and transcript level (Figure 1c)
Summary
The American Cancer Society estimates that in 2016, about 246,660 women will be diagnosed with breast cancer and approximately 40,450 women will die of the disease in the United States (American Cancer Society, Cancer Facts & Figures, 2016). Breast cancer is the second leading cause of cancer-related death among women in the United States. It is imperative to identify relevant therapeutic targets that can inhibit metastasis of breast cancer. Epithelial-mesenchymal transition (EMT) enhances invasion and metastasis of cancer cells. EMT is widely accepted as a mechanism utilized by cancer cells to gain access to distant areas in the body [2,3,4,5]. Identifying distinctive molecules that regulate EMT and are “druggable” are critical to gain control of metastatic disease
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