ARYL-HYDROCARBON RECEPTOR-MEDIATED ANTIESTROGENICITY IN MCF-7 CELLS -MODULATION OF HORMONE-INDUCED CELL-CYCLE ENZYMES

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits 17 beta-estradiol (E2) mammary tumor growth in rodents and in MCF-7 human breast cancer cells; however, the cell cycle genes/proteins which are inhibited have not been determined, Initial studies showed that treatment of MCF-7 c ells with 10 nM E2 significantly increased cyclin D1 (protein and mRNA ), cdk2- and cdk4-dependent kinase activities, and hyperphosphorylatio n of retinoblastoma (RB) protein, In contrast to results of recent stu dies (M. D, Planas-Silva and R. A. Weinberg, 1997, Mol. Cell. Biol. 17 , 4059-4069), E2 induced dissociation of both cdk2 and cdk4 proteins f rom the p21 protein complex and significantly increased cdk7-dependent kinase activity. Treatment of MCF-7 cells with E2 also induced cdc25A phosphatase protein, which was accompanied by increased cdk2 and cdk4 proteins containing unphosphorylated tyrosine residues. Although TCDD alone has minimal effects on cell cycle proteins/enzymes, several E2- induced responses were significantly inhibited in MCF-7 cells cotreate d with E2 plus TCDD, For example, TCDD significantly inhibited E2-indu ced hyperphosphorylation of RB, cyclin D1 protein, and cdk2-, cdk4-, a nd cdk7-dependent kinase activities. Inhibition of E2-induced cdk4-dep endent kinase activity by TCDD may be related to the parallel decrease of E2-induced cyclin D1 protein, and inhibition of induced cdk2- and cdk4-dependent kinase activities may be due to significantly increased p21 levels in cells cotreated with TCDD plus E2. These results demons trate that the antiestrogenic activity of TCDD is due to downregulatio n of several E2-induced cell cycle proteins/activities and this illust rates the complex cross talk between the aryl hydrocarbon and the E2 r eceptor signaling pathways. (C) 1998 Academic Press.