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EDRI Federal Project Inventory:
60923-03 Mechanism of Hormonal Carcinogenesis in the Rat Prostate
- Sponsor Organization: NIH/NCI
- Project Title: 60923-03 MECHANISM OF HORMONAL CARCINOGENESIS IN THE RAT PROSTATE
- Project Focus: EXPOSURE ASSESSMENT, HUMAN HEALTH EFFECTS
- Description: We have obtained recent evidence that estrogens, per se or via
metabolic conversion, can cause genetic damage invivo and hence may
act as tumor initiators in the prostate. A rat model with features of
the human prostatic cancer isused as an experimental model of study.
Treatment of intact Noble (NBL) rats with testosterone (T) and
estradiol-17beta (E2beta) consistently induced a 100 67ysplasia and
adenocarcinoma in the dorsolateral lobe (DLP) of the ratgland.
Dysplasia was however, not induced when rats were exposed to T, DHT or
E2beta alone. We observed that theinduction of dysplasia was preceded
by the drastic increase in DLP mitotic activity and type II estrogen
receptor level. More recently, we found a significant increase in DNA
strand breaks and lipid peroxidation exclusively in DLPsharboring the
dysplasia. We therefore conclude that, in addition to mitogenic
action, the sex steroids may have directgenotoxicity in this prostatic
lobe. We hypothesize that the synergism between genetic and
epigenetic action of the sexhormones provides the mechanistic basis
of tumor initiation and promotion which eventually leads to
neoplastictransformation and tumor formation in rat DLP. In this
application we propose the following specific aims to evaluatethe
relative importance of the genotoxic and mitogenic action of sex
hormones in prostatic carcinogenesis in NBL rats: 1) to ascertain if
E2beta is the component in the E2beta treatment that actually induces
DNA damage in the rat DLP; 2)to evaluate whether the T + E2beta-
induced DNA damage in the rat DLP is a primary event induced by
E2betagenotoxicity and not a secondary phenomenon caused by cell
proliferation; 3) to determine whether the occurrence ofincrease in
DNA damage precedes the appearance of cell proliferation and dysplasia
and thereby provides evidence thatgenetic-damage is an event likely
involved in tumor initiation; 4) to examine if catechol estrogens
(CEs) formation is themetabolic step responsible for the conversion of
E2beta to DNA-reactive products in the DLP, but not in the VP, of
therat gland and to determine whether prostatic CE formation activity
in NBL rats is higher than that found in Sprague-Dawley (SD) rats.
This difference may then explain the difference in cancer
susceptibility of the two rat strains; 5) toassess the effectiveness
of T + diethylstilbestrol (DES, a synthetic estrogen with known
genotoxicity) treatment ininducing DNA damage, cell proliferation and
dysplasia in the two major prostatic lobes, VP and DLP, of the rat
gland.
- References:
- Category: MODELS
- Subcategory: BASIC RESEARCH
- Keywords for Experimental System/Species: LABORATORY STUDY, IN VIVO
- Keywords for Experimental Endpoints: CARCINOGENESIS
- Chemical Agents: SEX HORMONES, ESTROGENS, TESTOSTERONE, ESTRADIOL-17BETA (E2BETA),
DIETHYLSTILBESTROL (DES)
- Performing Institution: TUFTS UNIVERSITY MEDFORD
- Contact: CONTACT PERSON: ELAINE C. LEE; BUILDING 31; 11A21, NATIONAL CANCER
INSTITUTE, NIH,BETHESDA, MD 20892-2590; 301 496-5515;
LEEE@0D.NCI.NIH.GOV
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