Antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Effect on expression of pS2, a prognostic marker for human breast cancer

Conference · Sun Dec 31 04:00:00 EST 1995

OSTI ID:244867

Gillesby, B E; Wu, Z F; Zacharewski, T ^[1]; Stanostefano, M; Safe, S ^[2]

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1. Univ. of Western Ontario, London, Ontario (Canada). Dept. of Pharmacology and Toxicology
2. Texas A and M Univ., College Station, TX (United States). Dept. of Veterinary Physiology and Pharmacology

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds modulate endocrine systems by altering hormone synthesis, enhancing ligand metabolism and down-regulating receptor levels and binding activity. Previous studies have demonstrated that TCDD inhibits the 17{beta}-estradiol (E2)-induction of pS2, a prognostic marker for breast cancer. This effect occurs at the transcriptional level and is an Ah receptor-mediated process. Computer analysis of the regulatory region identified three dioxin response element (DRE)-like motifs each containing a perfectly conserved DRE core. In order to identify the motif which mediated this inhibition, transient transfection experiments were performed in MCF-7 human breast cancer cells using pS2-regulated luciferase reporter genes. Deletion analysis indicates that the DRE-like motif (IDRE) located at {minus}527 to {minus}514 is required for TCOD-mediated suppression of E2-induced reporter gene activity. The introduction of a point mutation within this core motif (T to C at position {minus}518) abolishes the suppressive effects, further supporting a role for the IDRE- in the antiestrogenic activity of TCDD. UV-induced protein-DNA cross-linking studies and gel retardation assays demonstrate that the IDRE could bind and compete with the consensus DRE for Ah receptor complex binding. These results suggest that Ah receptor complexes interact with a specific motif in the 51 regulatory region to suppress E2-induction of pS2 expression. Therefore, the inhibition of gene expression may also contribute to the antiestrogenic activities of TCOD and related compounds.

• OSTI ID: 244867
• Report Number(s): CONF-9511137--; ISBN 1-880611-03-1
• Country of Publication: United States
• Language: English

Related Subjects

56 BIOLOGY AND MEDICINE
APPLIED STUDIES
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL MARKERS
BIOSYNTHESIS
CARCINOGENESIS
DIOXIN
ESTRADIOL
GENE MUTATIONS
GENE REGULATION
INHIBITION
MAMMARY GLANDS
MAN
NEOPLASMS
RECEPTORS