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Endoplasmic reticulum protein 29 regulates epithelial cell integrity during the mesenchymal–epithelial transition in breast cancer cells

Oncogene volume 32, pages 1240–1251 (2013)Cite this article

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Abstract

The epithelial–mesenchymal transition (EMT) correlates with disruption of cell–cell adhesion, loss of cell polarity and development of epithelial cell malignancy. Identifying novel molecules that inhibit EMT has profound potential for developing mechanism-based therapeutics. We previously demonstrated that the endoplasmic reticulum protein 29 (ERp29) is a novel factor that can drive mesenchymal–epithelial transition (MET) and induce cell growth arrest in MDA-MB-231 cells. Here, we show that ERp29 is an important molecule in establishing epithelial cell integrity during the MET. We demonstrate that ERp29 regulates MET in a cell context-dependent manner. ERp29 overexpression induced a complete MET in mesenchymal MDA-MB-231 cells through downregulating the expression of transcriptional repressors (for example, Slug, Snai1, ZEB2 and Twist) of E-cadherin. In contrast, overexpression of ERp29 induces incomplete MET in basal-like BT549 cells in which the expression of EMT-related markers (for example, vimentin; cytokeratin 19 (CK19) and E-cadherin) and the transcriptional repressors of E-cadherin were not altered. However, ERp29 overexpression in both cell-types resulted in loss of filamentous stress fibers, formation of cortical actin and restoration of an epithelial phenotype. Mechanistic studies revealed that overexpression of ERp29 in both cell-types upregulated the expression of TJ proteins (zonula-occludens-1 (ZO-1) and occludin) and the core apical–basal polarity proteins (Par3 and Scribble) at the membrane to enhance cell–cell contact and cell polarization. Knockdown of ERp29 in the epithelial MCF-7 cells decreased the expression of these proteins, leading to the disruption of cell–cell adhesion. Taken together, ERp29 is a novel molecule that regulates MET and epithelial cell integrity in breast cancer cells.

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Acknowledgements

DRR thanks the National Health and Medical Research Council of Australia for a Senior Principal Research Fellowship. This research was performed in DZ’s laboratory in the National University of Singapore and was sponsored by an Individual Research Grant awarded to DZ from the Agency of Science, Technology and Research-Biomedical Research Council in Singapore (A*STAR-BMRC 07/1/21/19/496).

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Authors and Affiliations

  1. Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    I F Bambang & D Zhang

  2. Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    I F Bambang & Y K Lee

  3. Department of Pathology and Bosch Institute, Iron metabolism and Chelation Program, University of Sydney, Sydney, New South Wales, Australia

    D R Richardson & D Zhang

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  1. I F Bambang
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Correspondence to D R Richardson or D Zhang.

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Bambang, I., Lee, Y., Richardson, D. et al. Endoplasmic reticulum protein 29 regulates epithelial cell integrity during the mesenchymal–epithelial transition in breast cancer cells. Oncogene 32, 1240–1251 (2013). https://doi.org/10.1038/onc.2012.149

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