Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent

Davis, F.M., Azimi, I., Faville, R.A., Peters, A.A., Jalink, K., Putney Jr, J.W., Goodhill, G.J., Thompson, E.W., Roberts-Thomson, S.J., & Monteith, G.R. (2014) Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent. Oncogene, 33, pp. 2307-2316.

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Abstract

Signals from the tumor microenvironment trigger cancer cells to adopt an invasive phenotype through epithelial-mesenchymal transition (EMT). Relatively little is known regarding key signal transduction pathways that serve as cytosolic bridges between cell surface receptors and nuclear transcription factors to induce EMT. A better understanding of these early EMT events may identify potential targets for the control of metastasis. One rapid intracellular signaling pathway that has not yet been explored during EMT induction is calcium. Here we show that stimuli used to induce EMT produce a transient increase in cytosolic calcium levels in human breast cancer cells. Attenuation of the calcium signal by intracellular calcium chelation significantly reduced epidermal growth factor (EGF)- and hypoxia-induced EMT. Intracellular calcium chelation also inhibited EGF-induced activation of signal transducer and activator of transcription 3 (STAT3), while preserving other signal transduction pathways such as Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. To identify calcium-permeable channels that may regulate EMT induction in breast cancer cells, we performed a targeted siRNA-based screen. We found that transient receptor potential-melastatin-like 7 (TRPM7) channel expression regulated EGF-induced STAT3 phosphorylation and expression of the EMT marker vimentin. Although intracellular calcium chelation almost completely blocked the induction of many EMT markers, including vimentin, Twist and N-cadherin, the effect of TRPM7 silencing was specific for vimentin protein expression and STAT3 phosphorylation. These results indicate that TRPM7 is a partial regulator of EMT in breast cancer cells, and that other calcium-permeable ion channels are also involved in calcium-dependent EMT induction. In summary, this work establishes an important role for the intracellular calcium signal in the induction of EMT in human breast cancer cells. Manipulation of calcium-signaling pathways controlling EMT induction in cancer cells may therefore be an important therapeutic strategy for preventing metastases.

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67 citations in Scopus
59 citations in Web of Science®
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ID Code: 71136
Item Type: Journal Article
Refereed: Yes
Additional Information: Cited By (since 1996):6
Export Date: 6 May 2014
Source: Scopus
Article in Press
DOI: 10.1038/onc.2013.187
ISSN: 0950-9232
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Deposited On: 07 May 2014 01:53
Last Modified: 21 Jun 2017 05:02

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