BACKGROUND: The estrogen receptor (ER) is a ligand-dependant transcription 
factor expressed in many breast cancers and is the target of many 
endocrine-based cancer therapies. Genome-wide studies have shown that the ER 
binds to gene-specific enhancer regions in response to β-estradiol (E2) which 
undergo transcription producing noncoding enhancer RNA (eRNA). While eRNAs are 
important for transcriptional activation of neighboring genes, the mechanism 
remains poorly understood.
RESULTS: Using ChIP-Seq we generate a global profile of thymine DNA glycosylase 
(TDG), an ER coactivator that plays an essential role in DNA demethylation, in 
response to E2 in the MCF7 breast cancer cell line. Remarkably, we found that in 
response to E2 TDG localized to enhancers which also recruit ERα, RNA Pol II and 
other coregulators and which are marked by histone modifications indicative of 
active enhancers. Importantly, depletion of TDG inhibits E2-mediated 
transcription of eRNAs and transcription of ER-target genes. Functionally, we 
find that TDG both sensitizes MCF7 cells to tamoxifen-mediated cytostasis and 
increases migration and invasion of MCF7 cells.
CONCLUSIONS: Taken together we find that TDG plays a central role in mediating 
transcription at a subset of enhancers and governs how MCF7 cells respond to 
both estrogenic and anti-estrogenic compounds and may be an effective 
therapeutic target.