TY - JOUR
T1 - Global gene expression analysis of estrogen receptor transcription factor cross talk in breast cancer
T2 - Identification of estrogen-induced/activator protein-1-dependent genes
AU - DeNardo, David G.
AU - Kim, Hee Tae
AU - Hilsenbeck, Susan
AU - Cuba, Valerie
AU - Tsimelzon, Anna
AU - Brown, Powel H.
PY - 2005/2
Y1 - 2005/2
N2 - There is a growing body of literature supporting estrogen's ability to affect gene expression through a nonclassical pathway, in which estrogen receptor (ER) modulates the activity of other transcription factors such as activator protein (AP)-1, specificity protein (Sp-1), or nuclear factor-κB (NFκB). We hypothesized that many estrogen-induced genes are dependent on AP-1 for their expression and that these genes can be identified using genomic strategies. Using cells expressing an inducible cJun dominant negative, we studied the estrogen induction of genes under conditions in which AP-1 was normal or blocked. We show that the expression of AP-1-dependent genes was inhibited by the cJun dominant negative and that AP-1 blockade does not affect mRNA ERα expression or estrogen induction of estrogen-responsive element activity. Using a microarray approach, we then identified 20 new estrogen-induced/AP-1-dependent genes. These estrogen-induced/AP-1-dependent genes contain a higher frequency of consensus AP-1 sites in their promoters and have increased sensitivity to the AP-1 stimulant tetradecanoyl phorbol acetate when compared with estrogen-induced genes whose expression was not affected by AP-1 blockade. We also show estrogen and AP-1-dependent recruitment of ER, steroid receptor coactivator-1, and p300 to the promoter of these genes by chromatin immunoprecipitation. These studies demonstrate that microarrays can be used in a reverse genetics approach to predict the functional promoter structure of large numbers of genes that are regulated by multiple transcription factors.
AB - There is a growing body of literature supporting estrogen's ability to affect gene expression through a nonclassical pathway, in which estrogen receptor (ER) modulates the activity of other transcription factors such as activator protein (AP)-1, specificity protein (Sp-1), or nuclear factor-κB (NFκB). We hypothesized that many estrogen-induced genes are dependent on AP-1 for their expression and that these genes can be identified using genomic strategies. Using cells expressing an inducible cJun dominant negative, we studied the estrogen induction of genes under conditions in which AP-1 was normal or blocked. We show that the expression of AP-1-dependent genes was inhibited by the cJun dominant negative and that AP-1 blockade does not affect mRNA ERα expression or estrogen induction of estrogen-responsive element activity. Using a microarray approach, we then identified 20 new estrogen-induced/AP-1-dependent genes. These estrogen-induced/AP-1-dependent genes contain a higher frequency of consensus AP-1 sites in their promoters and have increased sensitivity to the AP-1 stimulant tetradecanoyl phorbol acetate when compared with estrogen-induced genes whose expression was not affected by AP-1 blockade. We also show estrogen and AP-1-dependent recruitment of ER, steroid receptor coactivator-1, and p300 to the promoter of these genes by chromatin immunoprecipitation. These studies demonstrate that microarrays can be used in a reverse genetics approach to predict the functional promoter structure of large numbers of genes that are regulated by multiple transcription factors.
UR - http://www.scopus.com/inward/record.url?scp=13544270852&partnerID=8YFLogxK
U2 - 10.1210/me.2004-0267
DO - 10.1210/me.2004-0267
M3 - Article
C2 - 15514030
AN - SCOPUS:13544270852
SN - 0888-8809
VL - 19
SP - 362
EP - 378
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 2
ER -