ERR β signalling through FST and BCAS2 inhibits cellular proliferation in breast cancer cells

Abstract

Background:

The overexpression of oestrogen-related receptor- β (ERR β) in breast cancer patients is correlated with improved prognosis and longer relapse-free survival, and the level of ERR β mRNA is inversely correlated with the S-phase fraction of cells from breast cancer patients.

Methods:

Chromatin immunoprecipitation (ChIP) cloning of ERR β transcriptional targets and gel supershift assays identified breast cancer amplified sequence 2 ( BCAS2) and Follistatin (FST) as two important downstream genes that help to regulate tumourigenesis. Confocal microscopy, co-immunoprecipitation (CoIP), western blotting and quantitative real-time PCR confirmed the involvement of ERR β in oestrogen signalling.

Results:

Overexpressed ERR β induced FST-mediated apoptosis in breast cancer cells, and E-cadherin expression was also enhanced through upregulation of FST. However, this anti-proliferative signalling function was challenged by ERR β-mediated BCAS2 upregulation, which inhibited FST transcription through the downregulation of β-catenin/TCF4 recruitment to the FST promoter. Interestingly, ERR β-mediated upregulation of BCAS2 downregulated the major G1-S transition marker cyclin D1, despite the predictable oncogenic properties of BCAS2.

Interpretation:

Our study provides the first evidence that ERR β, which is a coregulator of ER α also acts as a potential tumour-suppressor molecule in breast cancer. Our current report also provides novel insights into the entire cascade of ERR β signalling events, which may lead to BCAS2-mediated blockage of the G1/S transition and inhibition of the epithelial to mesenchymal transition through FST-mediated regulation of E-cadherin. Importantly, matrix metalloprotease 7, which is a classical mediator of metastasis and E-cadherin cleavage, was also restricted as a result of ERR β-mediated FST overexpression.