2103

ESRRB

BACKGROUND: The overexpression of oestrogen-related receptor-beta (ERRbeta) in breast cancer patients is correlated with improved prognosis and longer relapse-free survival, and the level of ERRbeta mRNA is inversely correlated with the S-phase fraction of cells from breast cancer patients. METHODS: Chromatin immunoprecipitation (ChIP) cloning of ERRbeta 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 ERRbeta in oestrogen signalling. RESULTS: Overexpressed ERRbeta 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 ERRbeta-mediated BCAS2 upregulation, which inhibited FST transcription through the downregulation of beta-catenin/TCF4 recruitment to the FST promoter. Interestingly, ERRbeta-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 ERRbeta, which is a coregulator of ERalpha also acts as a potential tumour-suppressor molecule in breast cancer. Our current report also provides novel insights into the entire cascade of ERRbeta 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 ERRbeta-mediated FST overexpression.