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Molecular aspects of antiestrogen resistance and autophagy in breast cancer cells
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Text
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Title
Molecular aspects of antiestrogen resistance and autophagy in breast cancer cells
SubTitle
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ETD_1759
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http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051386
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eng
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theses
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(authority = RUETD)
Topic
Nutritional Sciences
Subject
(ID = SBJ-2);
(authority = ETD-LCSH)
Topic
Estrogen--Antagonists
Subject
(ID = SBJ-3);
(authority = ETD-LCSH)
Topic
Cell death
Subject
(ID = SBJ-4);
(authority = ETD-LCSH)
Topic
Breast--Cancer--Endocrine aspects
Abstract
The major objective of this thesis was to examine the molecular aspects of estrogenic growth and autophagy in estrogen receptor α (ERα)-positive breast cancer cells. We first examined the role of autophagy mediator, Beclin 1, in estrogenic signaling and antiestrogen resistance in Beclin 1-overexpressing MCF-7 cells. We found that a potential interaction between ERα and Beclin 1 rendered Beclin 1-transfected cells less sensitive to estradiol (E2)-induced growth stimulation, and to antiestrogen-mediated growth inhibition. Thus, a novel function for Beclin 1 might involve down-regulation of the action of ERα, contributing to resistance of breast cancer cells to antiestrogens.
In an attempt to develop novel therapeutic agents for breast cancer, we explored the effect of the polyamine analogue, 1,15-bis(ethylamino)-4,8,12-triazapentadecane (BE-3-3-3-3), on MCF-7 cell growth in the presence and absence of E2. BE-3-3-3-3 caused growth inhibition in the presence of E2. However, it mimicked estradiol and stimulated cell growth in the absence of E2, and induced growth response genes, such as c-fos, c-jun, and c-myc. This also induced autophagy, and increased levels of autophagy-related proteins, Beclin 1 and MAP LC3-II.
In another approach to introduce gene therapy for breast cancer treatment, we explored the physico-chemical aspects of DNA nanoparticle formation. In an effort to optimize gene delivery systems, we investigated DNA condensation to nanoparticles in the presence of α,α'-methylated spermine analogues, and characterized the size, shape and stability of the resultant nanoparticles. Although some analogues proved more efficacious DNA condensing agents than
spermine, hydrodynamic radii of nanoparticles produced by analogues were comparable to those produced by spermine.
We also compared the DNA condensing abilities of poly-L-lysine (PLL) and oligolysines, and characterized the physico-chemical properties of their condensates. PLL was a more effective condensing agent than oligolysines, and produced more stable nanoparticles. We conclude that PLL and oligolysines bind and condense DNA through different mechanisms.
In summary, our research provides new insights into the mechanism of antiestrogen resistance and autophagy in breast cancer. We also provide mechanistic insight into DNA nanoparticle formation in the presence of polyamine analogues and lysines.
In an attempt to develop novel therapeutic agents for breast cancer, we explored the effect of the polyamine analogue, 1,15-bis(ethylamino)-4,8,12-triazapentadecane (BE-3-3-3-3), on MCF-7 cell growth in the presence and absence of E2. BE-3-3-3-3 caused growth inhibition in the presence of E2. However, it mimicked estradiol and stimulated cell growth in the absence of E2, and induced growth response genes, such as c-fos, c-jun, and c-myc. This also induced autophagy, and increased levels of autophagy-related proteins, Beclin 1 and MAP LC3-II.
In another approach to introduce gene therapy for breast cancer treatment, we explored the physico-chemical aspects of DNA nanoparticle formation. In an effort to optimize gene delivery systems, we investigated DNA condensation to nanoparticles in the presence of α,α'-methylated spermine analogues, and characterized the size, shape and stability of the resultant nanoparticles. Although some analogues proved more efficacious DNA condensing agents than
spermine, hydrodynamic radii of nanoparticles produced by analogues were comparable to those produced by spermine.
We also compared the DNA condensing abilities of poly-L-lysine (PLL) and oligolysines, and characterized the physico-chemical properties of their condensates. PLL was a more effective condensing agent than oligolysines, and produced more stable nanoparticles. We conclude that PLL and oligolysines bind and condense DNA through different mechanisms.
In summary, our research provides new insights into the mechanism of antiestrogen resistance and autophagy in breast cancer. We also provide mechanistic insight into DNA nanoparticle formation in the presence of polyamine analogues and lysines.
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electronic resource
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xi, 141 p. : ill.
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Note
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Ph.D.
Note
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Includes bibliographical references
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by Irina Nayvelt
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Nayvelt
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Irina
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1977
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Irina Nayvelt
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Thomas
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T. J.
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chair
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Advisory Committee
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T. J. Thomas
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Thomas
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Thresia
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Advisory Committee
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Thresia Thomas
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Shapses
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Sue
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Sue Shapses
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Dixon
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Joseph
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Joseph Dixon
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Ganesan
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Shridar
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Shridar Ganesan
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Rutgers University
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degree grantor
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Graduate School - New Brunswick
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2009
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2009-05
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xx
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Rutgers University Electronic Theses and Dissertations
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ETD
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Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
Identifier
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doi:10.7282/T32N52G8
Genre
(authority = ExL-Esploro)
ETD doctoral
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The author owns the copyright to this work.
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Copyright protected
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Open
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Non-exclusive ETD license
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Author Agreement License
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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