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Nkx3-1 and LEF-1 Function as Transcriptional Inhibitors of Estrogen Receptor Activity

¹ Cancer Research UK, Cambridge Research Institute, Cambridge, United Kingdom; Departments of ² Biostatistics and Computational Biology and ³ Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School; ⁴ Harvard School of Public Health, Boston, Massachusetts; and ⁵ The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey

Requests for reprints: Jason Carroll, Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, United Kingdom. Phone: 44-1223-404510; Fax: 44-1223-404199; E-mail: jason.carroll{at}cancer.org.uk.

Key Words: Estrogen Receptor • LEF-1 • Nkx3-1

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. [Cancer Res 2008;68(18):7380–5]

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