Antiestrogenic and antimitogenic effects of 2,3,7,8-Tetrachlorodibenzo-para-dioxin (TCDD) : in vitro mechanistic studies

Abstract

2,3,7,8 -Tetrachlorodibenzo-p-dioxin (TCDD) is a broad spectrum antiestrogen which works through the aryl hydrocarbon (Ah) receptor. The estrogen receptor (ER) positive hum an ovarian carcinoma cell lines PE01, PE04 and PE06 expressed the Ah receptor with properties similar to the AhR from other human cells. However, TCDD-induced P450IA1 mRNA levels, ethoxyresorufin O-deethylase (EROD) activity and an AhR-DRE complex only in the PEO4 cells. 17β-Estradiol (E2) stimulated PEO4 and PEO6 cell proliferation and the E2-induced cell growth was suppressed by TCDD in both of these cell lines. These data show that TCDD exhibits antiestrogenic activity in ER-positive ovarian carcinoma cell lines which is not dependent on P450IA1 induction. The antiestrogenic and antimitogenic activity of TCDD was investigated in the E2 responsive MCF-7 hum an breast cancer cells. TCDD suppressed E2-, IGF-1-, Insulin-, E2 plus IGF-1- and E2 plus Insulin-induced cell proliferation. The steady-state mRNA levels for the ER and IGF-1 receptor were not effected by TCDD or any other treatments. However, TCDD inhibited E2-induced pS2 mRNA steady-state levels and the constitutive expresion of HER -2/neu receptor mRNA steady-state levels were suppressed after TCDD-treatment. TCDD-inhibited or suppressed E2-induced expression of immediate early oncogenes c-myc and c-fos and TPA and E2-induced AP-l-TRE binding. Alternatively, treatment of MCF-7 cells with TPA-inhibited TCDD-induced AhR-DRE binding and expression of Fos oncoprotein suppressed TCDD dependent AhR transactivation of a CAT reporter gene in both MCF-7 and Hepa 1c1c7 cells. Moreover, in Hepa 1c1c 7 cells, Fos and Jun inhibited the formation of a TCDD-dependent AhR-DRE complex and AhR was precipitated with Fos antibodies. These results were consistent with the formation of a nuclear Ah receptor-Fos complex and support a novel mechanism to explain some fo the antimitogenic and antiestrogenic effects of TCDD.