Co-regulated gene expression by oestrogen receptor α and liver receptor homolog-1 is a feature of the oestrogen response in breast cancer cells.
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.
Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK, Department of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands and Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
Chun-Fui
CF
Lai
Koen D
KD
Flach
Xanthippi
X
Alexi
Stephen P
SP
Fox
Silvia
S
Ottaviani
Paul T R
PT
Thiruchelvam
Fiona J
FJ
Kyle
Ross S
RS
Thomas
Rosalind
R
Launchbury
Hui
H
Hua
Holly B
HB
Callaghan
Jason S
JS
Carroll
R
R
Charles Coombes
Wilbert
W
Zwart
Laki
L
Buluwela
Simak
S
Ali
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D061986:MCF-7 Cells; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020218:Response Elements
D047628:Estrogen Receptor alpha; C082631:NR5A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear