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Title:Integration of Nuclear- and Extranuclear-Initiated Estrogen Receptor Signaling in Breast Cancer Cells
Author(s):Madak Erdogan, Zeynep
Doctoral Committee Chair(s):Kemper, Byron W.
Department / Program:Cell and Developmental Biology
Discipline:Cell and Developmental Biology
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Biology, Molecular
Biology, Cell
Abstract:Estrogenic hormones exert their effects through binding to Estrogen Receptors (ERs), which work in concert with coregulators and extranuclear signaling pathways to control gene expression in normal as well as cancerous states, including breast tumors. In this thesis, we have used multiple genome-wide analysis tools to elucidate various ways that are utilized by extranuclear-initiated estrogen receptor pathways to impact gene expression in MCF-7 breast cancer cells.
In the first part of the thesis, in order to investigate the impact of estrogen-mediated extranuclear-initiated pathways on global gene expression, we used estrogen-dendrimer conjugates (EDCs), which, because of their charge and size, remain outside the nucleus and can only initiate extranuclear signaling. We showed that inputs from both nuclear and extranuclear ER signaling pathways are important in regulating patterns of gene expression in breast cancer cells.
In the second part of the thesis, in order to identify ERalpha and ERK2 binding sites after E2 and EDC treatment in MCF-7 cells, we performed chromatin immunoprecipitation (ChIP) followed by genome-wide microarray analysis. We found that ERK2 binding sites are associated with E2 regulated genes as well as genes whose expression correlates with ER expression in breast tumors and ncRNAs, which thus might impact tumor physiology and progression at multiple levels.
In the third part of the thesis, in order to elucidate the mechanisms that the MAPK pathway utilizes to impact ERalpha action in breast cancer cells, we compared the gene expression profiles of MCF-7 cells to that of MCF-7 cells where ERK1 or ERK2 were depleted using RNAi technology. Our findings revealed that ERK1 and ERK2 regulate distinct sets of physiological processes by modulating basal expression as well as E2-mediated transcriptional regulation of many critical target genes in breast cancer cells.
In the final part of the thesis, we focused on the crosstalk between ERalpha and Aryl Hydrocarbon Receptor (AhR). Our data suggest that a tertiary complex forms between ERalpha, AhR and RIP140 and this complex, possibly through switching the function of one of ERalpha coregulators from a coactivator to a corepressor, controls the magnitude and duration of ERalpha-mediated gene stimulation.
Issue Date:2009
Description:172 p.
Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2009.
Other Identifier(s):(UMI)AAI3392205
Date Available in IDEALS:2014-12-17
Date Deposited:2009

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