Epithelial-mesenchymal transition in breast epithelial cells treated with cadmium and the role of Snail

Abstract

Epidemiological and experimental studies have implicated cadmium (Cd) with breast cancer. In breast epthelial MCF10A and MDA-MB-231 cells, Cd has been shown to promote cell growth. The present study examined whether Cd also causes epithelial-mesenchymal transition (EMT), a hallmark of cancer progression. Human breast epithelial cells consisting of non-cancerous MCF10A, non-metastatic HCC 1937 and HCC 38, and metastatic MDA-MB-231 were treated with 1 or 3 μM Cd for 4 weeks. The MCF10A epithelial cells switched to a more mesenchymal-like morphology, which was accompanied by a decrease in the epithelial marker E-cadherin and an increase in the mesenchymal markers N-cadherin and vimentin. In both non-metastatic HCC 1937 and HCC 38 cells, treatment with Cd decreased the epithelial marker claudin-1. In addition, E-cadherin also decreased in the HCC 1937 cells. Even the mesenchymal-like MDA-MB-231 cells exhibited an increase in the mesenchymal marker vimentin. These changes indicated that prolonged treatment with Cd resulted in EMT in both normal and cancer-derived breast epithelial cells. Furthermore, both the MCF10A and MDA-MB-231 cells labeled with Zcad, a dual sensor for tracking EMT, demonstrated a decrease in the epithelial marker E-cadherin and an increase in the mesenchymal marker ZEB-1. Treatment of cells with Cd significantly increased the level of Snail, a transcription factor involved in the regulation of EMT. However, the Cd-induced Snail expression was completely abolished by actinomycin D. Luciferase reporter assay indicated that the expression of Snail was regulated by Cd at the promotor level. Snail was essential for Cd-induced promotion of EMT in the MDA-MB-231 cells, as knockdown of Snail expression blocked Cd-induced cell migration. Together, these results indicate that Cd promotes EMT in breast epithelial cells and does so by modulating the transcription of Snail.

Cadmium and Lead Decrease Cell–Cell Aggregation and Increase Migration and Invasion in Renca Mouse Renal Cell Carcinoma Cells

“…These effects may involve wnt/β-catenin signaling and Snail expression [19,20]. Similar effects-decreased E-cadherin and increased n-cadherin expression-were also seen in MCF10A breast epithelial cells challenged with cadmium [20]. These in vitro studies are also supported by in vivo data.…”

“…MDA-MB-231 breast cancer cells challenged with low levels of cadmium (1-3 µM) for 8 weeks exhibited increased proliferation and migration, and EMT as evidenced by decreased E-cadherin expression and increased n-cadherin, Twist and slug expression [18]. These effects may involve wnt/β-catenin signaling and Snail expression [19,20]. Similar effects-decreased E-cadherin and increased n-cadherin expression-were also seen in MCF10A breast epithelial cells challenged with cadmium [20].…”

The Effects of Trifolium pratense L. Sprouts’ Phenolic Compounds on Cell Growth and Migration of MDA-MB-231, MCF-7 and HUVEC Cells

“…The MCF-7 cell line is reported as an ER-positive cellular model, whereas MDA-MB-231 is an ER-negative one (but with positive vimentin expression, which along with N-cadherin, is found in invasive and motile cells) [48]. Human endothelial HUVEC cells are known to express both ER isoforms [48]. Surprisingly, research presented by us revealed that all of the cell lines express ERα and ERβ mRNA (Figure 8).…”

“…Simultaneously, isolated phenolics at comparable dosages revealed no toxicity against normal HUVEC cells. That can be connected not only with different cellular type, but also with the potential expression of both ER-receptor isoforms [48].…”

“…In our further studies we want to examine T. pratense extracts' influence on ER expression in different cells. The MCF-7 cell line is reported as an ER-positive cellular model, whereas MDA-MB-231 is an ER-negative one (but with positive vimentin expression, which along with N-cadherin, is found in invasive and motile cells) [48]. Human endothelial HUVEC cells are known to express both ER isoforms [48].…”