Global Uterine Genomics in Vivo: Microarray Evaluation of the Estrogen Receptor α-Growth Factor Cross-Talk Mechanism

Cross-talk between growth factor receptors and the estrogen receptor (ER) has been proposed as a signaling mechanism in estrogen target tissues, with ERα as a direct target of growth factor receptor-activated signals, leading to regulation of estrogen target genes and estrogen-like biological respon...

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Bibliographic Details
Published in:Molecular endocrinology (Baltimore, Md.) Md.), 2005-03, Vol.19 (3), p.657-668
Main Authors: Curtis Hewitt, Sylvia, Collins, Jennifer, Grissom, Sherry, Deroo, Bonnie, Korach, Kenneth S
Format: Article
Language:English
Subjects:
Alternative Splicing
Animals
Blotting, Northern
Blotting, Western
Cluster Analysis
DNA, Complementary - metabolism
Down-Regulation
Estradiol - metabolism
Estrogen Receptor alpha - genetics
Female
Genomics
Growth Substances - metabolism
Humans
MAP Kinase Signaling System
Mice
Models, Biological
Oligonucleotide Array Sequence Analysis
Phosphatidylinositol 3-Kinases - metabolism
Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Time Factors
Up-Regulation
Uterus - metabolism
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Summary:Cross-talk between growth factor receptors and the estrogen receptor (ER) has been proposed as a signaling mechanism in estrogen target tissues, with ERα as a direct target of growth factor receptor-activated signals, leading to regulation of estrogen target genes and estrogen-like biological responses to growth factors. We evaluated whether global genomic changes in the mouse uterus in response to epidermal growth factor or IGF-I mimic those of estradiol (E2), reflecting the cross-talk mechanism. Overlapping responses to growth factors and E2 were expected in the wild type (WT) whereas no response was expected in mice lacking ERα (ERα knockout). Surprisingly, although most of the E2 response in the WT also occurred after growth factor treatment, some genes were induced only by E2. Second, although E2 did not induce gene changes in the αER knockout, the growth factor response was almost indistinguishable from that of the WT. Differences in response of some genes to IGF-I or epidermal growth factor indicated selective regulation mechanisms, such as phosphatidylinositol 3-kinase or MAPK-dependent responses. The robust ERα-independent genomic response to growth factor observed here is surprising considering that the biological growth response is ERα dependent. We propose two mechanisms as alternatives to the cross-talk mechanism for uterine gene regulation. First, E2 increases uterine growth factors, which activate downstream signaling cascades, resulting in gene regulation. Second, growth factors and estrogen regulate similar genes. Our results suggest that the estrogen response in the uterus involves E2-specific ERα-mediated responses as well as responses resulting from convergence of growth factor and ER-initiated activities.
ISSN:0888-8809
1944-9917
DOI:10.1210/me.2004-0142