Identification of novel ER-alpha target genes in breast cancer cells: gene- and cell-selective co-regulator recruitment at target promoters determines the response to 17beta-estradiol and tamoxifen.
Tamoxifen and 17beta-estradiol are capable of up-regulating the expression of some genes and down-regulate the expression of others simultaneously in the same cell. In addition, tamoxifen shows distinct transcriptional activities in different target tissues. To elucidate whether these events are determined by differences in the recruitment of co-regulators by activated estrogen receptor-alpha (ER-alpha) at target promoters, we applied chromatin immunoprecipitation (ChIP) with promoter microarray hybridisation in breast cancer T47D cells and identified 904 ER-alpha targets genome-wide. On a selection of newly identified targets, we show that 17beta-estradiol and tamoxifen stimulated up- or down-regulation of transcription correlates with the selective recruitment of co-activators or co-repressors, respectively. This is shown for both breast (T47D) and endometrial carcinoma cells (ECC1). Moreover, differential co-regulator recruitment also explains that tamoxifen regulates a number of genes in opposite direction in breast and endometrial cancer cells. Over-expression of co-activator SRC-1 or co-repressor SMRT is sufficient to alter the transcriptional action of tamoxifen on a number of targets. Our findings support the notion that recruitment of co-regulator at target gene promoters and their expression levels determine the effect of ER-alpha on gene expression to a large extent.
Romano
Andrea
A
GROW, School for Oncology and Developmental Biology, Maastricht University Medical Centre, 6202 AZ Maastricht, The Netherlands. a.romano@og.unimaas.nl
Adriaens
Michiel
M
Kuenen
Sabine
S
Delvoux
Bert
B
Dunselman
Gerard
G
Evelo
Chris
C
Groothuis
Patrick
P
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D014158:Transcription, Genetic
D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D013629:Tamoxifen; D004958:Estradiol