title: Nkx3-1 and LEF-1 function as transcriptional inhibitors of estrogen receptor activity.
abstract: Estrogen receptor (ER)-associated cofactors and cooperating transcription factors are one of the primary components determining transcriptional activity of estrogen target genes and may constitute potential therapeutic targets. Recent mapping of ER-binding sites on a genome-wide scale has provided insight into novel cooperating factors based on the enrichment of transcription factor motifs within the ER-binding sites. We have used the ER-binding sites in combination with sequence conservation to identify the statistical enrichment of Nkx and LEF motifs. We find that Nkx3-1 and LEF-1 bind to several ER cis-regulatory elements in vivo, but they both function as transcriptional repressors of estrogen signaling. We show that Nkx3-1 and LEF-1 can inhibit ER binding to chromatin, suggesting competition for common chromatin-binding regions. These data provide insight into the role of Nkx3-1 and LEF-1 as potential regulators of the hormone response in breast cancer.
authors.affiliation: Cancer Research UK, Cambridge Research Institute, Cambridge, United Kingdom.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Holmes
authors.forename: Jun S
authors.initials: JS
authors.lastname: Song
authors.forename: Xiaole S
authors.initials: XS
authors.lastname: Liu
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.forename: Jason S
authors.initials: JS
authors.lastname: Carroll
mesh_terms: D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010957:Plasmids / Q000235:genetics; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; C491178:NKX3-1 protein, human; C102837:Nkx3-1 protein, mouse; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D014157:Transcription Factors