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Title: | Modulation of gene expression by estrogen and protein kinase activators in MCF-7 human breast cancer cells |
Author(s): | Cho, Hyeseong |
Doctoral Committee Chair(s): | Katzenellenbogen, Benita S. |
Department / Program: | Molecular and Integrative Physiology |
Discipline: | Molecular and Integrative Physiology |
Degree Granting Institution: | University of Illinois at Urbana-Champaign |
Degree: | Ph.D. |
Genre: | Dissertation |
Subject(s): | Biology, Molecular
Biology, Cell Biology, Animal Physiology |
Abstract: | My thesis research involved studying hormonal modulation of gene expression in three different cases in MCF-7 human breast cancer cells, which contain high levels of estrogen receptor and low levels of progesterone receptor. Regulation of the pS2 gene was no longer stimulated by estradiol (E$\sb2$) in the E$\sb2$ growth-independent MCF-7 cell subline (MCF-7 K3) while expression of the pS2 gene was under the direct control of estrogen in the E$\sb2$ growth-dependent MCF-7 subline (MCF-7 k1). In contrast, progesterone receptor (PR) and estrogen receptor (ER) retained normal patterns of regulation by E$\sb2$. This altered regulation of the pS2 gene is probably not caused either by a defect of the ER or by changes in trans-acting factors in the MCF-7 K3 subline. Although PR is known to be primarily up-regulated by E$\sb2$, alternate signal transduction pathways also increased cellular PR content in MCF-7 cells. Increases in PR protein levels by insulin/IGF-1 (insulin-like growth factor-1) were not accompanied by PR mRNA stimulation while PR mRNA levels were markedly induced by E$\sb2$ and protein kinase A activator. The increase in PR mRNA by protein kinase A activator was almost completely abolished by treatment with antiestrogen and required ongoing protein synthesis. I also found that serum factor(s) actively interfere with the action of cAMP on regulation of PR. Hence, multihormonal regulation of PR may explain the existence of receptor phenotypes in breast cancer that are ER-negative and PR-positive. Activators of protein kinase A and C markedly synergized with E$\sb2$ in ER-mediated transcriptional activation in MCF-7 cells. This synergistic stimulation most likely does not come from changes in cellular ER content or changes in binding affinity of ER for ligand or DNA, but rather may be a consequence of a stabilization of the interaction of ER with target components of the transcriptional machinery. Protein kinase C activator showed cell- and promoter-specific effects on ER-mediated transcriptional activation. |
Issue Date: | 1992 |
Type: | Text |
Language: | English |
URI: | http://hdl.handle.net/2142/23167 |
Rights Information: | Copyright 1992 Cho, Hyeseong |
Date Available in IDEALS: | 2011-05-07 |
Identifier in Online Catalog: | AAI9236424 |
OCLC Identifier: | (UMI)AAI9236424 |
This item appears in the following Collection(s)
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Dissertations and Theses - Molecular and Integrative Physiology
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Graduate Dissertations and Theses at Illinois
Graduate Theses and Dissertations at Illinois