The effect of TCDD and related compounds on 17B-estradiol-induced secretion of procathepsin D (52-kDa) protein in MCF-7 human breast cancer cells : mechanistic studies

Abstract

TCDD is a broad spectrum antiestrogen and mediates its antiestrogenic effects through the aryl hydrocarbon receptor (AhR). 176-estradiol (E2) induces the secretion of procathepsin D, a 52-kDa protein in MCF-7 human breast cancer cells. TCDD inhibits the E2-induced secretion of 52-kDa protein in MCF-7 human breast cancer cells. Initial studies focused on the development of a unique gel staining bioassay for measurement of secreted levels of 52-kDa from MCF-7 human breast cancer cells. This assay was extensively used to investigate the antiestrogenic activity of diverse polychlorinated and polycyclic aromatic hydrocarbons. The results of quantitative structure-activity studies further supported a role for the AhR in mediating inhibition of E2-induced 52-kDa secretion in MCF-7 cells. Furthermore, it was demonstrated that TCDD inhibited E2- induced formation of cytosolic cathepsin-D, cath-D gene transcription and cath-D promoter activity. Subsequent studies demonstrated that E2 regulates cath-D gene transcription through an ER/Spl complex and inhibition of E2-induced gene transcription by TCDD is due to disruption of the ER/Spl complex through a xenobiotic response element which is strategically located between the ER and Spl DNA binding sites. These data suggest a unique mechanism of action for the AhR which acts as a ligand-induced transcription attenuator. This novel mechanism may be involved in TCDD-mediated inhibition of other E2-induced genes.