2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin (TCDD) and Related Compounds as Antioestrogens: Characterization and Mechanism of Action

Abstract: In the female Sprague‐Dawley rat uterus 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) and related compounds exhibited a broad spectrum of antioestrogenic responses. For example 2,3,7,8‐TCDD inhibited the 17β‐oestradiol‐induced uterine wet weight increase, peroxidase activity, oestrogen and progesterone receptor levels, epidermal growth factor (EGF) receptor binding, and EGF receptor and c‐fos protooncogene mRNA levels. The aryl hydrocarbon (Ah) receptor was identified in the rat uterus and the antioestrogenic activities of TCDD and related compounds were structure‐dependent. In parallel studies, the effects of TCDD as an antioestrogen in MCF‐7 human breast cancer cells was also investigated. TCDD inhibited the 17β‐oestradiol‐induced proliferation of these cells and the secretion of the 34‐, 52‐ and 160‐kDa proteins. Treatment of MCF‐7 cells with 1 nM [³H]‐β‐oestradiol resulted in a rapid accumulation of nuclear oestrogen receptor (ER) complexes. Pretreatment of the cells with TCDD caused a rapid decrease in nuclear ER binding activity and immunoreactive protein; moreover, the structure‐dependent potencies of TCDD and related compounds as antioestrogens were similar to their Ah receptor binding affinities. TCDD also caused a decrease in nuclear ER levels in wild‐type Ah‐responsive Hepa lclc7 cells but was inactive in Ah non‐responsive mutant Hepa lclc7 cells. Moreover, in the wild‐type cells, both antinomycin D and cycloheximide blocked the effects of TCDD. 6‐Methyl‐1,3,8‐trichlorodibenzofuran (MCDF) has previously been characterized as a TCDD antagonist in rodents and in transformed rodent cell lines. However, like TCDD, MCDF also exhibited a broad spectrum of antioestrogenic activities in both the female Sprague‐Dawley rat uterus and MCF‐7 cells. MCDF is relatively non‐toxic compared to TCDD and is being investigated as a compound which may be clinically useful for the treatment of mammary cancer. 1991 Nordic Pharmacological Society