Aryl hydrocarbon receptor-mediated antiestrogenicity in MCF-7 cells: Modulation of hormone-induced cell cycle enzymes

Weili Wang, Roger Smith, Stephen Safe

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits 7β-estradiol (E2) mammary tumor growth in rodents and in MCF-7 human breast cancer cells; however, the ell cycle genes/proteins which are inhibited have not been determined. Initial studies showed that treatment of MCF-7 cells with 10 nM E2 significantly increased cyclin D1 (protein and mRNA), cdk2- and dk4- dependent kinase activities, and hyperphosphoylation of retinoblastoma (RB) protein. In contrast to results of recent studies (M.D. Planas-Silva and R. A. Weinberg, 1997, Mol. Cell. Biol. 17, 4059-4069), E2 induced dissociation of both cdk2 and cdk4 proteins 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 ells cotreated with E2 plus TCDD. For example, TCDD significantly inhibited E2- induced hyperphosphorylation of RB, cyclin D1 protein, and cdk2-, cdk4-, and cdk7-dependent kinase activities. Inhibition of E2-induced cdk4-dependent 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 demonstrate that the antiestrogenic activity of TCDD is due to downregulation of several E2- induced cell cycle proteins/activities and this illustrates the complex cross talk between the aryl hydrocarbon and the E2 receptor signaling pathways.

Original languageEnglish (US)
Pages (from-to)239-248
Number of pages10
JournalArchives of Biochemistry and Biophysics
Volume356
Issue number2
DOIs
StatePublished - Aug 15 1998

Keywords

  • 2,3,7,8-tetrachlorodibenzo-p-dioxin
  • Cell cycle
  • Cross-talk mechanisms
  • Estrogen

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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