Co-regulated gene expression by oestrogen receptor α and liver receptor homolog-1 is a feature of the oestrogen response in breast cancer cells.

Abstract

Oestrogen receptor α (ERα) is a nuclear receptor that is the driving transcription factor expressed in the majority of breast cancers. Recent studies have demonstrated that the liver receptor homolog-1 (LRH-1), another nuclear receptor, regulates breast cancer cell proliferation and promotes motility and invasion. To determine the mechanisms of LRH-1 action in breast cancer, we performed gene expression microarray analysis following RNA interference for LRH-1. Interestingly, gene ontology (GO) category enrichment analysis of LRH-1-regulated genes identified oestrogen-responsive genes as the most highly enriched GO categories. Remarkably, chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) to identify genomic targets of LRH-1 showed LRH-1 binding at many ERα binding sites. Analysis of select binding sites confirmed regulation of ERα-regulated genes by LRH-1 through binding to oestrogen response elements, as exemplified by the TFF1/pS2 gene. Finally, LRH-1 overexpression stimulated ERα recruitment, while LRH-1 knockdown reduced ERα recruitment to ERα binding sites. Taken together, our findings establish a key role for LRH-1 in the regulation of ERα target genes in breast cancer cells and identify a mechanism in which co-operative binding of LRH-1 and ERα at oestrogen response elements controls the expression of oestrogen-responsive genes.

• Authors: Chun-Fui Lai, Koen D Flach, Xanthippi Alexi, Stephen P Fox, Silvia Ottaviani, Paul T R Thiruchelvam, Fiona J Kyle, Ross S Thomas, Rosalind Launchbury, Hui Hua, Holly B Callaghan, Jason S Carroll, R Charles Coombes, Wilbert Zwart, Laki Buluwela, Simak Ali
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 41 Issue 22 Pg. 10228-40 (Dec 2013) ISSN: 1362-4962 [Electronic] England
• PMID: 24049078 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogen Receptor alpha
• NR5A2 protein, human
• Receptors, Cytoplasmic and Nuclear

Topics

• Animals
• Breast Neoplasms (genetics, metabolism)
• COS Cells
• Chlorocebus aethiops
• Estrogen Receptor alpha (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• MCF-7 Cells
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Response Elements