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

Br J Cancer. 2014 Apr 15;110(8):2144-58. doi: 10.1038/bjc.2014.53. Epub 2014 Mar 25.


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

Methods: Chromatin immunoprecipitation (ChIP) cloning of ERRβ 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 ERRβ in oestrogen signalling.

Results: Overexpressed ERRβ 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 ERRβ-mediated BCAS2 upregulation, which inhibited FST transcription through the downregulation of β-catenin/TCF4 recruitment to the FST promoter. Interestingly, ERRβ-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 ERRβ, which is a coregulator of ERα also acts as a potential tumour-suppressor molecule in breast cancer. Our current report also provides novel insights into the entire cascade of ERRβ 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 ERRβ-mediated FST overexpression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Epithelial-Mesenchymal Transition / genetics
  • Estrogen Receptor alpha / genetics
  • Female
  • Follistatin / biosynthesis*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neoplasm Proteins / biosynthesis*
  • Promoter Regions, Genetic
  • Receptors, Estrogen / biosynthesis
  • Receptors, Estrogen / genetics*
  • Signal Transduction
  • Transcriptional Activation
  • beta Catenin / genetics


  • BCAS2 protein, human
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • FST protein, human
  • Follistatin
  • Neoplasm Proteins
  • Receptors, Estrogen
  • beta Catenin
  • estrogen receptor-related receptor beta