ERbeta1 represses basal breast cancer epithelial to mesenchymal transition by destabilizing EGFR

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
Breast Cancer Research: BCR 2012 November 16, 14 (6): R148

INTRODUCTION: Epithelial to mesenchymal transition (EMT) is associated with the basal-like breast cancer phenotypes. 60% of basal-like cancers have been shown to express wild-type estrogen receptor beta (ERbeta1). However, it is still unclear whether the ERbeta expression is related to EMT, invasion and metastasis in breast cancer. In the present study, we examined whether ERbeta1 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 ERbeta1 was either overexpressed or downregulated 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). Coimmunoprecipitation and ubiquitylation assays were employed to examine whether ERbeta1 alters EGFR protein degradation and the interaction between EGFR and the ubiquitin ligase c-Cbl. The metastatic potential of the ERbeta1-expressing MDA-MB-231 cells was evaluated in vivo in a zebrafish xenotransplantation model and the correlation between ERbeta1 and E-cadherin expression was examined in 208 clinical breast cancer specimens by immunohistochemistry.

RESULTS: Here we show that ERbeta1 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 ERbeta1-mediated upregulation 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 ERbeta1 and E-cadherin expression was additionally observed in breast tumor samples. Downregulation 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 ERbeta1-mediated repression of EMT and induction of EGFR signaling abolished the ability of ERbeta1 to sustain the epithelial phenotype.

CONCLUSIONS: Taken together, the results of our study strengthen the association of ERbeta1 with the regulation of EMT and propose the receptor as a potential crucial marker in predicting metastasis in breast cancer.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"