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EDRI Federal Project Inventory:
70708-01 Cadmium and Breast Cancer Etiology
- Sponsor Organization: NIH/NCI
- Project Title: 70708-01 CADMIUM AND BREAST CANCER ETIOLOGY
- Project Focus: EXPOSURE ASSESSMENT, HUMAN HEALTH EFFECTS
- Description: One of the most prevalent of cancers, breast cancer, is characterized
by hormonal control of its growth. In cellculture, estrogens control
the proliferation and differentiation of human breast cancer cells.
Recent data from theprincipal investigator's laboratory demonstrate
that the heavy metal, cadmium, mimics the effects of estradiol in
humanbreast cancer cells, in the uterus in organ culture, and in
ovariectomized animals, suggesting a role for cadmium in
thedevelopment of breast cancer. In MCF-7 breast cancer cells,
cadmium decreased the steady state level of estrogenreceptor,
increased the steady state level of progesterone receptor, pS2, and
cathepsin D, and induced cell growth.Cadmium also activated a GAL-ER
chimeric receptor containing the DNA binding domain of the yeast
transcriptionfactor, GAL4, and the hormone binding domain of the
estrogen receptor. The results of these studies suggest that
theeffects of cadmium are mediated through the hormone binding domain
of the estrogen receptor independent of estradiolbinding. In
ovariectomized rats, cadmium had a mitogenic effect on the uterus.
In organ culture, cadmium induced twoestrogen responsive genes in the
mouse uterus suggesting that cadmium also mimics the effects of
estradiol on theuterus and the effects are a direct effect. A recent,
very large hypothesis-generating case-control study derived
fromoccupational coding of death certificates found an excess risk
of breast cancer associated with cadmium exposure.Taken together,
these data suggest that environmental exposure to cadmium activates
the estrogen receptor and leads toan increased risk of breast cancer.
The aims of this grant are three fold: 1) to define the role of
cadmium in thedevelopment of breast cancer; 2) to determine the
mechanism of activation of the estrogen receptor by cadmium; and 3)to
determine whether other heavy metals are estrogenic. Aim 1 will test
whether cadmium mimics and/or enhances theeffects of estradiol in the
dimethylbenzanthracene (DMBA)-induced mammary tumor model system. This
aim will alsotest the hypothesis that women exposed to cadmium would
benefit from endocrine or other prevention treatment. Thestudies in
aim 2 are designed to determine whether: 1) cadmium activates the
estrogen receptor by a direct interactionwith the receptor, such as
interaction with thiol groups in the hormone binding domain of the
receptor or 2) cadmiumactivates the receptor by an indirect effect,
such as activation of signal transduction pathways to influence
thephosphorylation of the estrogen receptor. Aim 3 will test whether
other candidate heavy metals will activate theestrogen receptor.
- References:
- Category: MODELS
- Subcategory: BASIC RESEARCH
- Keywords for Experimental System/Species: LABORATORY STUDY, MAMMALIAN
- Keywords for Experimental Endpoints: HORMONE RECEPTORS, CARCINOGENESIS
- Chemical Agents: CADMIUM
- Performing Institution: GEORGETOWN UNIVERSITY
- Contact: CONTRACT 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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