title: ERRβ signalling through FST and BCAS2 inhibits cellular proliferation in breast cancer cells.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cancer Biology Laboratory, Department of Gene Function and Regulation, Institute of Life Sciences (an Institute under the Department of Biotechnology, Government of India), Nalco Square, Chandrasekharpur, Bhubaneswar, Odisha 751023, India.
authors.forename: D
authors.initials: D
authors.lastname: Sengupta
authors.affiliation: Cancer Biology Laboratory, Department of Gene Function and Regulation, Institute of Life Sciences (an Institute under the Department of Biotechnology, Government of India), Nalco Square, Chandrasekharpur, Bhubaneswar, Odisha 751023, India.
authors.forename: D K
authors.initials: DK
authors.lastname: Bhargava
authors.affiliation: Drug Design and Discovery, Department of Translational Research and Technology Development, Institute of Life Sciences (an Institute under the Department of Biotechnology, Government of India), Nalco Square, Chandrasekharpur, Bhubaneswar, Odisha 751023, India.
authors.forename: A
authors.initials: A
authors.lastname: Dixit
authors.affiliation: Confocal Microscopic Facility, Institute of Life Sciences (an Institute under the Department of Biotechnology, Government of India), Nalco Square, Chandrasekharpur, Bhubaneswar, Odisha 751023, India.
authors.forename: B S
authors.initials: BS
authors.lastname: Sahoo
authors.affiliation: Department of Pathology, Sparsh Hospitals and Critical Care, A/407, Saheed Nagar, Bhubaneswar, Odisha 751007, India.
authors.forename: S
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Department of Medical Oncology, Sparsh Hospitals and Critical Care, A/407, Saheed Nagar, Bhubaneswar, Odisha 751007, India.
authors.forename: G
authors.initials: G
authors.lastname: Biswas
authors.affiliation: Cancer Biology Laboratory, Department of Gene Function and Regulation, Institute of Life Sciences (an Institute under the Department of Biotechnology, Government of India), Nalco Square, Chandrasekharpur, Bhubaneswar, Odisha 751023, India.
authors.forename: S K
authors.initials: SK
authors.lastname: Mishra
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D038681:Follistatin / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D015533:Transcriptional Activation; D051176:beta Catenin / Q000235:genetics
chemical_list: C120624:BCAS2 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C503233:FST protein, human; D038681:Follistatin; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; D051176:beta Catenin; C107914:estrogen receptor-related receptor beta