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ERα signaling through slug regulates E-cadherin and EMT

Oncogene volume 29, pages 1451–1462 (2010)Cite this article

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Abstract

The ERα signaling pathway is one of the most important and most studied pathways in human breast cancer, yet numerous questions still exist such as how hormonally responsive cancers progress to a more aggressive and hormonally independent phenotype. We have noted that human breast cancers exhibit a strong direct correlation between ERα and E-cadherin expression by immunohistochemistry, suggesting that ERα signaling might regulate E-cadherin and implying that this regulation might influence epithelial–mesenchymal transition (EMT) and tumor progression. To investigate this hypothesis and the mechanisms behind it, we studied the effects of ERα signaling in ERα-transfected ERα-negative breast carcinoma cell lines, the MDA-MB-468 and the MDA-MB-231 and the effects of ERα knockdown in naturally expressing ERα-positive lines, MCF-7 and T47D. When ERα was overexpressed in the ERα-negative lines, 17β-estradiol (E2) decreased slug and increased E-cadherin. Clones maximally exhibiting these changes grew more in clumps and became less invasive in Matrigel. When ERα was knocked down in the ERα-positive lines, slug increased, E-cadherin decreased, cells became spindly and exhibited increased Matrigel invasion. ERα signaling decreased slug expression by two different mechanisms: directly, by repression of slug transcription by the formation of a corepressor complex of ligand-activated ERα, HDAC inhibitor (HDAC1), and nuclear receptor corepressor (N-CoR) that bound the slug promoter in three half-site estrogen response elements (EREs); indirectly by phosphorylation and inactivation of GSK-3β through phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt). The GSK-3β inactivation, in turn, repressed slug expression and increased E-cadherin. In human breast cancer cases, there was a strong inverse correlation between slug and ERα and E-cadherin immunoreactivity. Our findings indicate that ERα signaling through slug regulates E-cadherin and EMT.

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Acknowledgements

This study was supported by the Department of Defense Breast Cancer Research Program Grant W81XWH-06-1-0631, the Ohio State Strategic Initiative Grant Program and The Donald A Senhauser Endowment.

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Authors and Affiliations

  1. Department of Pathology, University of Nevada School of Medicine, Reno, NV, USA

    Y Ye & S H Barsky

  2. Department of Pathology, Nevada Cancer Institute, Las Vegas, NV, USA

    Y Ye & S H Barsky

  3. Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA

    Y Xiao, W Wang, K Yearsley, J X Gao & B Shetuni

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Correspondence to S H Barsky.

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Ye, Y., Xiao, Y., Wang, W. et al. ERα signaling through slug regulates E-cadherin and EMT. Oncogene 29, 1451–1462 (2010). https://doi.org/10.1038/onc.2009.433

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