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Breast Cancer Research
Published in: Breast Cancer Research 6/2012

Open Access 01-12-2012 | Research article

ERβ1 represses basal-like breast cancer epithelial to mesenchymal transition by destabilizing EGFR

Authors: Christoforos Thomas, Gayani Rajapaksa, Fotis Nikolos, Ruixin Hao, Anne Katchy, Catherine W McCollum, Maria Bondesson, Phil Quinlan, Alastair Thompson, Savitri Krishnamurthy, Francisco J Esteva, Jan-Åke Gustafsson

Published in: Breast Cancer Research | Issue 6/2012

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Abstract

Introduction

Epithelial to mesenchymal transition (EMT) is associated with the basal-like breast cancer phenotypes. Sixty percent of basal-like cancers have been shown to express wild-type estrogen receptor beta (ERβ1). However, it is still unclear whether the ERβ expression is related to EMT, invasion and metastasis in breast cancer. In the present study, we examined whether ERβ1 through regulating EMT can influence invasion and metastasis in basal-like cancers.

Methods

Basal-like breast cancer cells (MDA-MB-231 and Hs578T), in which ERβ1 was either overexpressed or down-regulated were analyzed for their ability to migrate and invade (wound-healing assay, matrigel-coated Transwell assay) as well as for the expression of EMT markers and components of the EGFR pathway (immunoblotting, RT-PCR). Co-immunoprecipitation and ubiquitylation assays were employed to examine whether ERβ1 alters epidermal growth factor receptor (EGFR) protein degradation and the interaction between EGFR and the ubiquitin ligase c-Cbl. The metastatic potential of the ERβ1-expressing MDA-MB-231 cells was evaluated in vivo in a zebrafish xenotransplantation model and the correlation between ERβ1 and E-cadherin expression was examined in 208 clinical breast cancer specimens by immunohistochemistry.

Results

Here we show that ERβ1 inhibits EMT and invasion in basal-like breast cancer cells when they grow either in vitro or in vivo in zebrafish. The inhibition of EMT correlates with an ERβ1-mediated up-regulation of miR-200a/b/429 and the subsequent repression of ZEB1 and SIP1, which results in increased expression of E-cadherin. The positive correlation of ERβ1 and E-cadherin expression was additionally observed in breast tumor samples. Down-regulation of the basal marker EGFR through stabilization of the ubiquitin ligase c-Cbl complexes and subsequent ubiquitylation and degradation of the activated receptor is involved in the ERβ1-mediated repression of EMT and induction of EGFR signaling abolished the ability of ERβ1 to sustain the epithelial phenotype.

Conclusions

Taken together, the results of our study strengthen the association of ERβ1 with the regulation of EMT and propose the receptor as a potential crucial marker in predicting metastasis in breast cancer.
Appendix
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Metadata
Title
ERβ1 represses basal-like breast cancer epithelial to mesenchymal transition by destabilizing EGFR
Authors
Christoforos Thomas
Gayani Rajapaksa
Fotis Nikolos
Ruixin Hao
Anne Katchy
Catherine W McCollum
Maria Bondesson
Phil Quinlan
Alastair Thompson
Savitri Krishnamurthy
Francisco J Esteva
Jan-Åke Gustafsson
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 6/2012
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3358

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