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EDRI Federal Project Inventory:
70655-01 Environmental Chemicals, Estrogens, and Breast Cancer
- Sponsor Organization: NIH/NCI
- Project Title: 70655-01 ENVIRONMENTAL CHEMICALS, ESTROGENS, AND BREAST CANCER
- Project Focus: HUMAN HEALTH EFFECTS
- Description: The search for etiologic factors that contribute to the development of
breast cancer has focused on environmentalchemical carcinogens,
environmental xenobiotics with estrogenic activity such as various
organochlorines, as well asincreased and/or inappropriate exposure to
endogenous estrogens or their metabolites. Several recent reports
havedemonstrated increased catechol metabolites of estrogens in urine
of women at increased risk for developing breastcancer, increased
oxidative DNA damage in breast tumor tissue and increased oxidative
DNA damage during estrogencarcinogenesis in animal model systems. In
addition, catechol estrogens can be oxidized by copper leading to
increasedoxidative DNA damage and the key catechol estrogen
inactivating enzyme, catechol O-methyltransferase (COMT) hasbeen shown
to be polymorphic with a fraction of women possessing low COMT
activity. The overall objective of thisproject is to begin to
investigate the following two hypotheses: 1) Exposure of normal and
tumorigenic breast epithelialtissue/cells to environmental chemicals
at low doses can induce cytochrome P450 activities which metabolize
estrogensto catechol metabolites resulting in increased oxidative
stress and damage, particularly in tissue/cells with low COMTactivity;
2) Oxidation of catechol estrogens, through a DNA-bound CuII/CuI-
dependent redox cycling process, causesincreased site-specific
oxidative DNA damage (strand breaks and increased levels of 8-hydroxy-
2'-deoxyguanosine (8-OH-dG)). Since catechol estrogens are estrogenic
the applicant hypothesizes that the estrogen receptor-estrogen-
catechol complex can cause, upon binding to the estrogen response
element of estrogen responsive genes, genepromoter-specific oxidative
damage through a DNA-bound CuII-dependent mechanism. The Specific Aims
are: 1) todetermine whether induction of P450 activity and/or
decreased catechol O-methyltransferase activity in human
breastepithelial cells leads to increased oxidative stress as
indicated by activation of NF-kb and c-fos expression and damagein
nuclear DNA as indicated by the appearance of strand breaks and
increased 8-OH-dG levels; 2) to determine ifcatechol estrogens,
through a DNA-bound CuII/Cul-dependent redox cycling process, can
cause increased site-specificoxidative DNA damage (strand breaks) and
whether the estrogen receptor-estrogen-catechol complex can, upon
bindingto the estrogen response element of estrogen responsive genes,
cause gene promoter-specific oxidative damage througha DNA-bound CuII-
dependent mechanism.
- References:
- Category: MODELS
- Subcategory: BASIC RESEARCH
- Keywords for Experimental System/Species: HUMAN, LABORATORY STUDY, IN VITRO
- Keywords for Experimental Endpoints: CARCINOGENESIS, XENOBIOTIC METABOLISM, GENE EXPRESSION, CYTOCHROME
P450
- Chemical Agents: ORGANOCHLORINES
- Performing Institution: JOHNS HOPKINS UNIVERSITY
- Contact: CONTACT PERSON: ELAINE C. LEE; BUILDING 31; 11A21, NATIONAL CANCER
INSTITUTE, NIH,BETHESDA, MD 20892-2590; 301- 496-5515;
LEEE@OD.NCI.NIH.GOV
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