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Holmes, KA, Song, JS, Liu, XS, Brown, M and Carroll, JS (2008) Nkx3-1 and LEF-1 function as transcriptional inhibitors of estrogen receptor activity. Cancer Res. 68:7380-5

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.

PubMed Online version:10.1158/0008-5472.CAN-08-0133

Animals; Binding Sites; Breast Neoplasms/genetics; Cell Line, Tumor; Chromatin/genetics; Chromatin/metabolism; Homeodomain Proteins/biosynthesis; Homeodomain Proteins/genetics; Homeodomain Proteins/metabolism; Humans; Lymphoid Enhancer-Binding Factor 1/biosynthesis; Lymphoid Enhancer-Binding Factor 1/genetics; Lymphoid Enhancer-Binding Factor 1/metabolism; Mice; Plasmids/genetics; Protein Binding; RNA, Small Interfering/genetics; Receptors, Estrogen/antagonists & inhibitors; Receptors, Estrogen/genetics; Receptors, Estrogen/metabolism; Transcription Factors/biosynthesis; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic; Transfection