Journal
BRITISH JOURNAL OF CANCER
Volume 110, Issue 8, Pages 2144-2158Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2014.53
Keywords
breast cancer; tumour suppressor; ERR beta; BCAS2; FST; apoptosis; metastasis
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Funding
- Department of Science and Technology
- Department of Biotechnology
- University Grants Commission, Government of India
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Background: The overexpression of oestrogen-related receptor-beta (ERR beta) in breast cancer patients is correlated with improved prognosis and longer relapse-free survival, and the level of ERR beta mRNA is inversely correlated with the S-phase fraction of cells from breast cancer patients. Methods: Chromatin immunoprecipitation (ChIP) cloning of ERR beta 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 beta in oestrogen signalling. Results: Overexpressed ERR beta 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 beta-mediated BCAS2 upregulation, which inhibited FST transcription through the downregulation of beta-catenin/TCF4 recruitment to the FST promoter. Interestingly, ERR beta-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 beta, which is a coregulator of ER alpha also acts as a potential tumour-suppressor molecule in breast cancer. Our current report also provides novel insights into the entire cascade of ERR beta 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 beta-mediated FST overexpression.
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