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TitleRedox cycling by catechol metabolites of endogenous estrogens as potential contributors to the initiation of breast cancer
NameFussell, Karma Claire (author), Laskin, Jeffrey D (chair), Gallo, Michael A (internal member), Gow, Andrew S (internal member), Gerecke, Donald R (internal member), Fan, Zhi-Hua (Tina) (outside member), Rutgers University, Graduate School - New Brunswick,
Degree Date2011-05
Date Created2011
SubjectToxicology,
Breast--Cancer ,
Estrogen
DescriptionHuman 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.
NotePh.D.
NoteIncludes bibliographical references
NoteIncludes vita
Noteby Karma Claire Fussell
Genretheses
Persistent URLhttp://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000061205
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.