Understanding how pioneer factors regulate estrogen receptor function in breast cancer cells


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Jason S Carroll, Kelly A Holmes

Cancer Research UK/Cambridge Research Institute, Cambridge, UK

Abstract

BACR/AstraZeneca Frank Rose Young Scientist Award

Background
Estrogen Receptor (ER) regulation of target gene transcription is a significant factor in breast cancer development and progression. Recent work in characterising ER transcriptional activity has suggested that ER regulates gene expression from distal cis-regulatory elements and uses a large number of co-factors for modulating chromatin. We recently showed that ER binding to chromatin requires a novel class of proteins called Pioneer factors. FoxA1 and GATA3 were shown to be Pioneer factors, required for ER to maintain binding to the DNA at a select number of tested regions. Recent work has suggested that Groucho/TLE proteins may have Pioneer properties.

Methods
We use genomic technologies, such as high throughput sequencing (Solexa sequencing) in combination with Chromatin Immunoprecipitations (ChIP) and DNase sensitivity assays. This allows us to map transcription factor binding sites and chromatin structure on a global level.

Results
We now show that the Groucho protein TLE1 is an ER Pioneer factor required for ER DNA interactions. Our data suggest that TLE1 is necessary for ER to bind to more than half the ER binding sites within the genome and for estrogen mediated transcriptional activity. Furthermore, TLE1 is essential for efficient estrogen-mediated cell cycle progression and can predict outcome in ER positive breast cancer patients. We also confirm on a genome-wide level that FoxA1 and GATA3 are critical determinants of ER binding to the chromatin and overall chromatin structure.

Conclusion
These data provide insight into the mechanisms by which ER maintains chromatin interactions and suggests that Pioneer factors may be critical determinants of ER function in breast cancer cells.