ANTIESTROGENIC ACTIVITIES OF ALTERNATE-SUBSTITUTED POLYCHLORINATED DIBENZOFURANS IN MCF-7 HUMAN BREAST-CANCER CELLS

Purpose: 1,3,6,8-Substituted alkyl polychlorinated dibenzofurans (PCDF s), typified by 6-methyl-1,3,8-triCDF (MCDF), inhibit 17 beta-estradio l (E2)-induced responses in the rodent uterus and human breast cancer cells. The major purpose of the experiments reported here was to deter mine the structure-dependent antiestrogenic activities of several alte rnate-substituted (1,3,6,8- and 2,4,6,8-) PCDFs. Methods: The antiestr ogenic activities were determined in MCF-7 human breast cancer cells u sing two assays, that is E2-induced cell proliferation and induction o f chloramphenicol acetyl transferase (CAT) activity in cells transient ly transfected with the E2-responsive Vit-CAT plasmid. Results: MCDF ( 10(-5) M), 6-isopropyl-1,3,8-triCDF, 6-ethyl-1,3,8-triCDF, 3-isopropyl -6-methyl-1,8-diCDF, and 6-methyl-2,4,8-triCDF, inhibited both E2-indu ced cell proliferation and CAT activity in MCF-7 cells. All of the rem aining ten congeners inhibited either E2-induced cell proliferation or CAT activity, but not both responses. Conclusions: The antiestrogenic activity of the alternate-substituted PCDFs involves interactions bet ween the aryl hydrocarbon and estrogen receptor signaling: pathways. A lthough these compounds exhibited antiestrogenic activity in MCF-7 cel ls, the effects of individual congeners were response-specific, and th ere were no apparent structure-activity relationships.