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Redox cycling by catechol metabolites of endogenous estrogens as potential contributors to the initiation of breast cancer
Descriptive
TitleInfo
Title
Redox cycling by catechol metabolites of endogenous estrogens as potential contributors to the initiation of breast cancer
Name
(type = personal)
NamePart
(type = family)
Fussell
NamePart
(type = given)
Karma Claire
NamePart
(type = date)
1981-
DisplayForm
Karma Fussell
Role
RoleTerm
(authority = RULIB)
author
Name
(type = personal)
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(type = family)
Laskin
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(type = given)
Jeffrey D
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Jeffrey D Laskin
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Advisory Committee
Role
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(authority = RULIB)
chair
Name
(type = personal)
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(type = family)
Gallo
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(type = given)
Michael A
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Michael A Gallo
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Advisory Committee
Role
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(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Gow
NamePart
(type = given)
Andrew S
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Andrew S Gow
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Advisory Committee
Role
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(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Gerecke
NamePart
(type = given)
Donald R
DisplayForm
Donald R Gerecke
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Fan
NamePart
(type = given)
Zhi-Hua (Tina)
DisplayForm
Zhi-Hua (Tina) Fan
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
outside member
Name
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NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB)
degree grantor
Name
(type = corporate)
NamePart
Graduate School - New Brunswick
Role
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(authority = RULIB)
school
TypeOfResource
Text
Genre
(authority = marcgt)
theses
OriginInfo
DateCreated
(qualifier = exact)
2011
DateOther
(qualifier = exact);
(type = degree)
2011-05
Place
PlaceTerm
(type = code)
xx
Language
LanguageTerm
(authority = ISO639-2b);
(type = code)
eng
Subject
(authority = RUETD)
Topic
Toxicology
RelatedItem
(type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier
(type = RULIB)
ETD
Note
(type = degree)
Ph.D.
Note
(type = bibliography)
Includes bibliographical references
Note
(type = vita)
Includes vita
Note
(type = statement of responsibility)
by Karma Claire Fussell
PhysicalDescription
Extent
xii, 162 p. : ill.
Form
(authority = gmd)
electronic resource
Abstract
(type = abstract)
Human idiopathic post-menopausal mammary adenocarcinoma is a tumor of breast epithelial tissue with a high incidence in women. The etiology of this disease stems from both genetic and environmental factors. A major environmental component thought to be
important in the development of breast cancer is estrogen exposure; indeed at least one environmental estrogen is known to have tumorigenic properties. Several studies have attempted to characterize the role of exogenous estrogens in initiating breast cancer;
however little work has been done using endogenous human estrogens. The present studies investigated a mechanism by which endogenous estrogens may contribute to idiopathic breast tumor formation. In this mechanism, endogenous estrogens are first
metabolized by cytochrome P450s to catechol metabolites. Catechols are known to be
reactive and can generate highly toxic and mutagenic reactive oxygen species (ROS) by redox cycling. We have shown that the flavoenzymes NADH-cytochrome b5 reductase and NADPH-cytochrome P450 reductase can mediate redox cycling of catechol estrogen metabolites and generate hydrogen peroxide, superoxide anion, and, under conditions favorable for Fenton chemistry, hydroxyl radicals. Moreover, we show that this process can damage DNA causing strand breakage and nucleotide base oxidation. We also
demonstrated that redox cycling by catechol metabolites of endogenous estrogens can occur in breast epithelial cells. Cell lysates from three human mammary epithelial cell lines, MCF-7 (estrogen receptor alpha positive, tumorigenic), MDA-MB-231 (estrogen
receptor alpha negative, tumorigenic), and MCF-10A (estrogen receptor alpha negative, non-tumorigenic), were found to redox cycle catechol estrogens and generate ROS. Additionally, these metabolites were found to stimulate hydrogen peroxide release by
intact cells as measured using an extracellular electrochemical microsensor. In all cases,
the three cell lines were found to be equally active in mediating redox cycling and generating ROS. These data indicate that redox cycling can occur in breast epithelial cells; however, ROS production appears to be independent of either estrogen receptor status or tumorigenic stage. Therefore, catechol estrogen metabolite redox cycling must be a constitutive property of the breast epithelial cells and is not acquired during breast tumor development. Because we can measure release of hydrogen peroxide by intact breast epithelial cells by catechol estrogens, redox cycling must be significant enough to overwhelm protective cellular antioxidant defense systems. Taken together, these data indicate that endogenous estrogen metabolism to catechols and subsequent flavoenzymemediated
redox cycling and generation of ROS may contribute to breast tumor development.
important in the development of breast cancer is estrogen exposure; indeed at least one environmental estrogen is known to have tumorigenic properties. Several studies have attempted to characterize the role of exogenous estrogens in initiating breast cancer;
however little work has been done using endogenous human estrogens. The present studies investigated a mechanism by which endogenous estrogens may contribute to idiopathic breast tumor formation. In this mechanism, endogenous estrogens are first
metabolized by cytochrome P450s to catechol metabolites. Catechols are known to be
reactive and can generate highly toxic and mutagenic reactive oxygen species (ROS) by redox cycling. We have shown that the flavoenzymes NADH-cytochrome b5 reductase and NADPH-cytochrome P450 reductase can mediate redox cycling of catechol estrogen metabolites and generate hydrogen peroxide, superoxide anion, and, under conditions favorable for Fenton chemistry, hydroxyl radicals. Moreover, we show that this process can damage DNA causing strand breakage and nucleotide base oxidation. We also
demonstrated that redox cycling by catechol metabolites of endogenous estrogens can occur in breast epithelial cells. Cell lysates from three human mammary epithelial cell lines, MCF-7 (estrogen receptor alpha positive, tumorigenic), MDA-MB-231 (estrogen
receptor alpha negative, tumorigenic), and MCF-10A (estrogen receptor alpha negative, non-tumorigenic), were found to redox cycle catechol estrogens and generate ROS. Additionally, these metabolites were found to stimulate hydrogen peroxide release by
intact cells as measured using an extracellular electrochemical microsensor. In all cases,
the three cell lines were found to be equally active in mediating redox cycling and generating ROS. These data indicate that redox cycling can occur in breast epithelial cells; however, ROS production appears to be independent of either estrogen receptor status or tumorigenic stage. Therefore, catechol estrogen metabolite redox cycling must be a constitutive property of the breast epithelial cells and is not acquired during breast tumor development. Because we can measure release of hydrogen peroxide by intact breast epithelial cells by catechol estrogens, redox cycling must be significant enough to overwhelm protective cellular antioxidant defense systems. Taken together, these data indicate that endogenous estrogen metabolism to catechols and subsequent flavoenzymemediated
redox cycling and generation of ROS may contribute to breast tumor development.
Subject
(authority = ETD-LCSH)
Topic
Breast--Cancer
Subject
(authority = ETD-LCSH)
Topic
Estrogen
Identifier
(type = hdl)
http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000061205
RelatedItem
(type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
(type = local)
rucore19991600001
Location
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(displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier
(type = doi)
doi:10.7282/T3XD1129
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
RightsDeclaration
(ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder
(type = personal)
Name
FamilyName
Fussell
GivenName
Karma
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
(encoding = w3cdtf);
(qualifier = exact);
(point = start)
2011-04-14 12:57:59
AssociatedEntity
Name
Karma Fussell
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
AssociatedObject
Type
License
Name
Author Agreement License
Detail
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.
RightsEvent
DateTime
(encoding = w3cdtf);
(qualifier = exact);
(point = start)
2011-05-31
DateTime
(encoding = w3cdtf);
(qualifier = exact);
(point = end)
2012-05-30
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 30th, 2012.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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