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An integrated network of estrogen receptors alpha and beta, and coregulators, for deciphering estrogen signaling in breast cancer cells

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Title: An integrated network of estrogen receptors alpha and beta, and coregulators, for deciphering estrogen signaling in breast cancer cells
Author(s): Charn, Tze Howe
Director of Research: Katzenellenbogen, John A.
Doctoral Committee Chair(s): Katzenellenbogen, John A.
Doctoral Committee Member(s): Katzenellenbogen, Benita S.; Zhong, Sheng; Wang, Yingxiao
Department / Program: Bioengineering
Discipline: Bioengineering
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Dissertation
Subject(s): Estrogen receptors MCF-7 nuclear receptor coactivator 3 (SRC3) RIP140
Abstract: The nuclear hormone receptors, ERα and ERβ, are known to regulate the transcriptional response programs of their target cells, including breast cancer cells. However, their comparative abilities to localize at chromatin binding sites across the genome, and the recruitment of major coregulators such as SRC3 and RIP140 by the ERs, and the association of ERs with other transcription factors and chromatin remodeling factors is incompletely understood. Therefore, in this report, we have used both chromatin immunoprecipitation (ChIP) on microarray (ChIP-chip) and ChIP sequencing (ChIP-seq) approaches in breast cancer cells containing three different complements of ERs (ERα alone, ERβ alone, or ERα + ERβ) treated with estradiol to define the cartography of chromatin binding sites for ERα, ERβ, and the coregulators SRC3 and RIP140. We found that ERα and ERβ bind to a similar, large number of sites in breast cancer cells containing only one ER subtype, but the two ERs appear to restrict each others chromatin binding and occupy fewer sites in cells containing both ERα and ERβ. We also observed that there are differences in term of enriched motifs in ERα and ERβ binding sites, with ERα binding sites enriched in GATA and FOXA1 motifs, whereas ERβ sites being preferentially enriched in E2F motifs. In addition, in cells containing both ERα and ERβ, ERα appears to displace ERβ so that ERβ binds to sites substantially less enriched in estrogen response element (ERE) sequence motifs. Gene chip microarray transcriptional profiling and gene ontology analysis delineated a core set of genes that correlate with ERα proliferative and ERβ anti-proliferative effects in breast cancer cells. ERβ activation by estradiol was associated with the inhibition of genes associated with cell proliferation and the up-regulation of pro-apoptotic genes and genes responding to DNA damage, whereas ERα activation was associated with the downregulation of pro-apoptotic genes and genes repressing transcription. Analysis of chromatin binding of SRC3 and RIP140 by ChIP-seq revealed that these coregulators are recruited preferentially to ER binding sites of estrogen-induced genes, whereas they are seldom recruited to ER binding sites of hormone-repressed genes, indicating that the SRC3-RIP140 complex is likely to be playing a central role in the induction of ER targeted genes. Our findings suggest an integrated model in which the actions of cofactors such as FOXA1, GATA3, and E2F enforce the selectivity and range of ERα and ERβ binding and gene regulatory actions, with the coregulators SRC3 and RIP140 preferentially supporting the stimulatory actions of both receptors on gene expression.
Issue Date: 2011-01-21
URI: http://hdl.handle.net/2142/18589
Rights Information: Copyright 2010 Tze Howe Charn
Date Available in IDEALS: 2011-01-21
2013-01-22
Date Deposited: 2010-12
 

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