1. Sponsor Organization: NIH/NIEHS

2. Project Title: 03561-11 DIOXIN/EPITHELIAL CELL INTERACTIONS--MECHANISM AND ASSAY

3. Project Focus:

• Project Primary Focus: Human Health Effects
• Project Secondary Focus:

4. Description:

The objective of this proposal is to determine the mechanism of regulation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) of estrogen dependent human breast cancer tumor growth in mice. TCDD inhibits the 17beta-estradiol (E2)-dependent postconfluent proliferation of MCF-7 human breast cancer cells in vitro. This effect is elicited though an Ah locus-mediated process which is coincident with depletion of E2 by increased metabolism. This project investigates whether the sensitivity and subsequent resistance to TCDD suppression of E2-dependent MCF-7 human breast tumor growth in vivo is initially due to TCDD-dependent, Ah locus mediated estrogen depletion in the tumor with subsequent enhancement of tumor sensitivity to E2 resulting from a compensatory increase in estrogen receptor levels. The following aims are proposed: 1) Determineif there is a requirement for Ah locus function in the host or tumor for sensitivity and resistance to TCDD suppression of E2-dependent MCF-7 tumor growth by use of mice and MCF-7 cells of various Ah locus competency. 2) Determine if the TCDD suppression of E2-dependent MCF-7 tumor growth is associated with E2 depletion by induced metabolism by measurement of E2 and E2 metabolism. 3) Determine if the estrogen receptor status of the TCDD resistant tumor is altered compared to non TCDD-treated tumors by measurement of estrogen receptor function, abundance, and synthesis.

5. References:

6. Inventory Category:

• Primary: Models
• Secondary:

7. Inventory Subcategory:

• Primary: Basic Research
• Secondary:

8. Keywords for Experimental System/Species:

• Species:
  • Mammal
  • Human
• Study Type:
  • Laboratory Study
• Fate and Transport:

9. Keywords for Experimental Endpoints:

• Health Effect:
• Hormonal Measures:
  • Hormone Receptors
• Level Of Study:
• Chemistry Metabolism:
  • Tissue Residue
  • Xenobiotic Metabolism
  • Exposure Monitoring
• Life Stage:
  • Growth
• Risk Assessment:
  • Risk Assessment, Carcinogenesis, Ah Receptor

10. Chemical Agents:

• Dioxins

11. Performing Institution:

• WADSWORTH CENTER FOR LABS AND RES

12. Contact:

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