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

作者：Sengupta D; Bhargava D K; Dixit A; Sahoo B S; Biswas S; Biswas G; Mishra S K^*

来源：British Journal of Cancer, 2014, 110(8): 2144-2158.

DOI：10.1038/bjc.2014.53

• breast cancer
• tumour suppressor
• ERR beta
• BCAS2
• FST
• apoptosis
• metastasis

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.

• 出版日期2014-4-15