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EDRI Federal Project Inventory:
70708-01 Cadmium and Breast Cancer Etiology



  1. Sponsor Organization: NIH/NCI

  2. Project Title: 70708-01 CADMIUM AND BREAST CANCER ETIOLOGY

  3. Project Focus: EXPOSURE ASSESSMENT, HUMAN HEALTH EFFECTS

  4. 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.

  5. References:

  6. Category: MODELS

  7. Subcategory: BASIC RESEARCH

  8. Keywords for Experimental System/Species: LABORATORY STUDY, MAMMALIAN

  9. Keywords for Experimental Endpoints: HORMONE RECEPTORS, CARCINOGENESIS

  10. Chemical Agents: CADMIUM

  11. Performing Institution: GEORGETOWN UNIVERSITY

  12. 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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