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EDRI Federal Project Inventory:
70466-01 Estrogen Epoxidation and Breast Cancer
- Sponsor Organization: NIH/NCI
- Project Title: 70466-01 ESTROGEN EPOXIDATION AND BREAST CANCER
- Project Focus: HUMAN HEALTH EFFECTS
- Description: Breast cancer leads all cancer incidence among American women,
accounting for 32 percent of the 1995 estimatednew cases in the United
States. It is the second leading cause of cancer deaths, estimated at
46,000 per year. Estrogens,natural or synthetic, used widely in a
variety of clinical conditions, from estrogen replacement therapy to
cancertreatment, are themselves carcinogenic, causing uterine, liver,
and breast cancers. However, the mechanism of theircarcinogenic
action is still not well understood. Because estrogens are required
for the growth and development oftarget cells, it has long been
believed that estrogens are promoters for carcinogenesis. Recent
studies have demonstratedthat estrogens are activated by the microsome
P450 enzymes to epoxides which are able to bind DNA, formingestrogen-
DNA adducts. These findings suggest the possibility that estrogens
may also be initiators for carcinogenesis. Taking advantage of our
experience during the past 15 years on aflatoxin B, research and
expertise in the applications ofmicrosome activation system, as well
as the extremely versatile epoxide-forming oxidant dimethyldioxane to
generateepoxides in vitro, we have synthesized the epoxides of the
commonly used estrogens: 17-beta- estradiol (E2),
estrone,diethylstilbestrol (DES) and tamoxifen (TAM). The specific
aims of this proposal are: (1) to study and compare thebinding
potentials and specificities of E2, estrone, DES and TAM epoxides on
several single- and double-strandedDNAs with known base content and
sequence and (2) to study and compare the relative transcriptional
effects of theseestrogen modified DNA templates on DNA-dependent RNA
synthesis. We believe that the results from these studieswill not
only shed new insights into the mechanism of actions and carcinogenic
potentials of these estrogens, but willalso help in the future
strategic planning for the proper clinical applications of these
estrogens.
- References:
- Category: MODELS
- Subcategory: BASIC RESEARCH
- Keywords for Experimental System/Species: IN VITRO, LABORATORY STUDY
- Keywords for Experimental Endpoints: CARCINOGENESIS , CYTOCHROME P450
- Chemical Agents: ESTRADIOL, DES, TAMOXIFEN
- Performing Institution: UNIVERSITY OF ILLINOIS AT CHICAGO
- 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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