Regular Article
Aryl Hydrocarbon Receptor-Mediated Antiestrogenicity in MCF-7 Cells: Modulation of Hormone-Induced Cell Cycle Enzymes,☆☆

https://doi.org/10.1006/abbi.1998.0782Get rights and content

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits 17β-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 cells with 10 nM E2 significantly increased cyclin D1 (protein and mRNA), cdk2- and cdk4-dependent kinase activities, and hyperphosphorylation 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 from 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 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.

References (62)

  • F. Parazzini et al.

    Gynecol. Oncol.

    (1991)
  • R. Clarke et al.

    Crit. Rev. Oncol. Hematol.

    (1992)
  • M.E. Lippman et al.

    Recent Prog. Horm. Res.

    (1989)
  • O.W.J. Prall et al.

    J. Biol. Chem.

    (1997)
  • R.L. Sutherland et al.

    Eur. J. Cancer Clin. Oncol.

    (1983)
  • E.A. Musgrove et al.

    Biochem. Biophys. Res. Commun.

    (1993)
  • S. Safe

    Pharmacol. Ther.

    (1995)
  • L. Biegel et al.

    J. Steroid Biochem. Mol. Biol.

    (1990)
  • P. Fernandez et al.

    Toxicol. Lett.

    (1992)
  • H. Liu et al.

    Mol. Cell. Endocrinol.

    (1992)
  • H. Liu et al.

    Toxicol. Appl. Pharmacol.

    (1996)
  • M. Moore et al.

    J. Biol. Chem.

    (1994)
  • R.J. Kociba et al.

    Toxicol. Appl. Pharmacol.

    (1978)
  • M. Holcomb et al.

    Cancer Lett.

    (1994)
  • A. McDougal et al.

    Cancer Lett.

    (1997)
  • Y.-F. Lu et al.

    Arch. Biochem. Biophys.

    (1996)
  • X. Wang et al.

    Mol. Cell. Endocrinol.

    (1993)
  • N. Harper et al.

    Mol. Cell. Endocrinol.

    (1994)
  • V. Krishnan et al.

    Anal. Biochem.

    (1992)
  • B.S. Katzenellenbogen et al.

    J. Steroid Biochem. Mol. Biol.

    (1995)
  • A.E. Wakeling

    Biochem. Pharmacol.

    (1995)
  • R.P. Fisher et al.

    Cell

    (1994)
  • D.M. Klotz et al.

    Biochem. Biophys. Res. Commun.

    (1995)
  • R.L. Sutherland et al.

    Hormones and Their Actions: Part I

    (1988)
  • B.S. Hulka
  • B.S. Hulka et al.

    Cancer

    (1994)
  • J. Russo et al.
  • J. Russo et al.

    Breast Cancer Res. Treat.

    (1996)
  • R.J. Santen et al.

    Endocr. Rev.

    (1990)
  • V.C. Jordan

    Breast Cancer Res. Treat.

    (1995)
  • Cited by (0)

    The financial assistance of the National Institutes of Health (CA-64081 and ES04176) and the Texas Agricultural Experiment Station is gratefully acknowledged.

    ☆☆

    Van der Molen, H. J.King, R. J. B.Cooke, B. A.

    2

    To whom correspondence should be addressed. Fax: (409) 862-4929. E-mail:[email protected].

    View full text