Discovery of estrogen receptor alpha target genes and response elements in breast tumor cells.
BACKGROUND
Estrogens and their receptors are important in human development, physiology and disease. In this study, we utilized an integrated genome-wide molecular and computational approach to characterize the interaction between the activated estrogen receptor (ER) and the regulatory elements of candidate target genes.


RESULTS
Of around 19,000 genes surveyed in this study, we observed 137 ER-regulated genes in T-47D cells, of which only 89 were direct target genes. Meta-analysis of heterogeneous in vitro and in vivo datasets showed that the expression profiles in T-47D and MCF-7 cells are remarkably similar and overlap with genes differentially expressed between ER-positive and ER-negative tumors. Computational analysis revealed a significant enrichment of putative estrogen response elements (EREs) in the cis-regulatory regions of direct target genes. Chromatin immunoprecipitation confirmed ligand-dependent ER binding at the computationally predicted EREs in our highest ranked ER direct target genes, NRIP1, GREB1 and ABCA3. Wider examination of the cis-regulatory regions flanking the transcriptional start sites showed species conservation in mouse-human comparisons in only 6% of predicted EREs.


CONCLUSIONS
Only a small core set of human genes, validated across experimental systems and closely associated with ER status in breast tumors, appear to be sufficient to induce ER effects in breast cancer cells. That cis-regulatory regions of these core ER target genes are poorly conserved suggests that different evolutionary mechanisms are operative at transcriptional control elements than at coding regions. These results predict that certain biological effects of estrogen signaling will differ between mouse and human to a larger extent than previously thought.
Lin
Chin-Yo
CY
Genome Institute of Singapore, Singapore 117528. lincy@gis.a-star.edu.sg
Ström
Anders
A
Vega
Vinsensius Berlian
VB
Kong
Say Li
SL
Yeo
Ai Li
AL
Thomsen
Jane S
JS
Chan
Wan Ching
WC
Doray
Balraj
B
Bangarusamy
Dhinoth K
DK
Ramasamy
Adaikalavan
A
Vergara
Liza A
LA
Tang
Suisheng
S
Chong
Allen
A
Bajic
Vladimir B
VB
Miller
Lance D
LD
Gustafsson
Jan-Ake
JA
Liu
Edison T
ET
D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000276:immunology; D047369:Chromatin Immunoprecipitation / Q000379:methods; D019295:Computational Biology / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics*; D016678:Genome; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011237:Predictive Value of Tests; D020218:Response Elements / Q000235:genetics*
D002843:Chromatin; D004273:DNA, Neoplasm; D047628:Estrogen Receptor alpha; D004958:Estradiol