Skip to main content
Log in

Mechanisms of Inhibitory Aryl Hydrocarbon Receptor-Estrogen Receptor Crosstalk in Human Breast Cancer Cells

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

The aryl hydrocarbon receptor (AhR)3 is a ligand-activated transcription factor that forms a functional heterodimeric complex with the AhR nuclear translocator (Arnt) protein. The environmental toxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is a high affinity ligand for the AhR and has been extensively used to investigate AhR-mediated biochemical and toxic responses. TCDD modulates several endocrine pathways including inhibition of 17β-estradiol-induced responses in the immature and ovariectomized rodent uterus and mammary gland and in human breast cancer cell lines. TCDD inhibits formation and growth of mammary tumors in carcinogen-induced rodent models and relatively nontoxic selective AhR modulators (SAhRMs) are being developed for treatment of breast cancer. The mechanisms of inhibitory AhR-estrogen receptor (ER) crosstalk have been investigated in MCF-7 breast cancer cells by analysis of promoter regions of genes induced by E2 and inhibited by TCDD. AhR-mediated inhibition of E2-induced cathepsin D, pS2, c-fos, and heat shock protein 27 gene expression involves direct interaction of the AhR complex with inhibitory pentanucleotide (GCGTG) dioxin responsive elements (iDREs) resulting in disruption of interactions between proteins binding DNA elements required for ER action and the basal transcription machinery. Mechanisms of inhibitory AhR-ER crosstalk indicate that functional iDREs are required for inhibition of some genes; however, results indicate that other interaction pathways are important including AhR-mediated proteasome-dependent degradation of the ER.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. E. J. Sondik (1994). Breast cancer trends. Incidence, mortality, and survival. Cancer 74:995–999.

    Google Scholar 

  2. B. S. Hulka, E. T. Liu, and R. A. Lininger (1994). Steroid hormones and risk of breast cancer. Cancer 74:1111–1124.

    Google Scholar 

  3. B. S. Hulka (1997). Epidemiologic analysis of breast and gynecologic cancers. In M. Aldaz, M. N. Gould, J. McLachlan, and T. J. Slaga (eds.), Etiology of Breast and Gynecological Cancers, Wiley-Liss, Inc., pp. 17–29.

  4. J. Russo and I. H. Russo (1997). Toward a unified concept of mammary carcinogenesis. In M. Aldaz, M. N. Gould, J. McLachlan, and T. J. Slaga (eds.), Etiology of Breast and Gynecological Cancers, Wiley-Liss, Inc., pp. 1–16.

  5. V. C. Jordan (1994). Molecular mechanisms of antiestrogen action in breast cancer. Breast Cancer Res. Treat. 31:41–52.

    Google Scholar 

  6. S. Safe (1995). Modulation of gene expression and endocrine response pathways by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds. Pharmacol. Therap. 67:247–281.

    Google Scholar 

  7. T. Zacharewski and S. Safe (1998). Antiestrogenic activity of TCDD and related compounds. In K. S. Korach (ed.), Reproductive and Developmental Toxicology, Marcel Dekker, Inc., New York, pp. 431–448.

    Google Scholar 

  8. W. Porter and S. Safe (1998). Estrogenic and antiestrogenic compounds. In A. Puga and K. B. Wallace (eds.), Molecular Biology Approaches to Toxicology, Techbooks, Fairfax, Virginia, pp. 267–283.

    Google Scholar 

  9. S. Safe (1999). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related environmental antiestrogens: Characterization and mechanism of action. In R. K. Naz (ed.), Endocrine Disruptors, CRC Press, Boca Raton, Florida, pp. 187–221.

    Google Scholar 

  10. S. Safe, C. Qin, and A. McDougal (1999). Development of selective aryl hydrocarbon receptor modulators (SARMs) for treatment of breast cancer. Expert Opin. Invest. Drugs 8:1385–1396.

    Google Scholar 

  11. A. Poland, E. Glover, and A. S. Kende (1976). Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol: Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J. Biol. Chem. 251:4936–4946.

    Google Scholar 

  12. A. Poland and J. C. Knutson (1982). 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons. Examinations of the mechanism of toxicity. Ann. Rev. Pharmacol. Toxicol. 22:517–554.

    Google Scholar 

  13. R. M. Evans (1988). The steroid and thyroid hormone receptor superfamily. Science 240:889–895.

    Google Scholar 

  14. M. Ema, K. Sogawa, N. Watanabe, Y. Chujoh, N. Matsushita, O. Gotoh, Y. Funae, and Y. Fujii-Kuriyama (1992). cDNA cloning and structure of the putative Ah receptor. Biochem. Biophys. Res. Commun. 184:246–253.

    Google Scholar 

  15. K. M. Burbach, A. B. Poland, and C. A. Bradfield (1992). Cloning of the Ah-receptor cDNA reveals a distinctive ligandactivated transcription factor. Proc. Natl. Acad. Sci. U.S.A 89:8185–8189.

    Google Scholar 

  16. E. C. Hoffman, H. Reyes, F.-F. Chu, F. Sander, L. H. Conley, B. A. Brooks, and O. Hankinson (1991). Cloning of a factor required for activity of the Ah (dioxin) receptor. Science 252:954–958.

    Google Scholar 

  17. C. L. Wilson and S. Safe (1998). Mechanisms of ligand-induced aryl hydrocarbon receptor-mediated biochemical and toxic responses. Toxicol. Pathol. 26:657–671.

    Google Scholar 

  18. M. R. Probst and O. Hankinson (1999). Interactions of ARNT with AhR and HIF-1α. In A. Puga and K. B. Wallace (eds.), Molecular Biology of the Toxic Response, Taylor and Francis, Philadelphia, pp. 377–392.

    Google Scholar 

  19. C. C. Abnet, R. L. Tanguay, M. E. Hahn, W. Heideman, and R. E. Peterson (1999). Two forms of aryl hydrocarbon receptor type 2 in rainbow trout (Oncorhynchus mykiss). Evidence for differential expression and enhancer specificity. J. Biol. Chem. 274:15159–15166.

    Google Scholar 

  20. E. Maltepe, J. V. Schmidt, D. Baunoch, C. A. Bradfield, and M. C. Simon (1997). Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature 386:403–407.

    Google Scholar 

  21. P. Fernandez-Salguero, T. Pineau, D. M. Hilbert, T. McPhail, S. S. Lee, S. Kimura, D. W. Nebert, S. Rudikoff, J. M. Ward, and F. J. Gonzalez (1995). Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 268:722–726.

    Google Scholar 

  22. J. V. Schmidt, G. H. Su, J. K. Reddy, M. C. Simon, and C. A. Bradfield (1996). Characterization of a murine Ahr null allele: Involvement of theAhreceptor in hepatic growth and development. Proc. Natl. Acad. Sci. U.S.A. 93:6731–6736.

    Google Scholar 

  23. J. P. Whitlock, S. T. Okino, L. Dong, H. P. Ko, R. Clarke-Katzenberg, Q. Ma, and H. Li (1996). Induction of cytochrome P4501A1: A model for analyzing mammalian gene transcription. FASEB J. 10:809–818.

    Google Scholar 

  24. A. Kobayashi, K. Numayamatsuruta, K. Sogawa, and Y. Fujii-Kuriyama (1997). CBP/p300 functions as a possible transcriptional coactivator of Ah receptor nuclear translocator (Arnt). J. Biochem. 122:703–710.

    Google Scholar 

  25. T. A. Nguyen, D. Hoivik, J. E. Lee, and S. Safe (1999). Interactions of nuclear receptor coactivator/corepressor proteins with the aryl hydrocarbon receptor complex. Arch. Biochem. Biophys. 367:250–257.

    Google Scholar 

  26. M. B. Kumar, R. W. Tarpey, and G. H. Perdew (1999). Differential recruitment of coactivator RIP140 by Ah and estrogen receptors: Absence of a role for LXXLL motifs. J. Biol. Chem. 274:22155–22164.

    Google Scholar 

  27. R. J. Kociba, D. G. Keyes, J. E. Beger, R. M. Carreon, C. E. Wade, D. A. Dittenber, R. P. Kalnins, L. E. Frauson, C. L. Park, S. D. Barnard, R. A. Hummel, and C. G. Humiston (1978). Results of a 2-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats. Toxicol. Appl. Pharmacol. 46:279–303.

    Google Scholar 

  28. M. Holcomb and S. Safe (1994). Inhibition of 7,12-dimethylbenzanthracene-induced rat mammary tumor growth by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Cancer Lett. 82:43–47.

    Google Scholar 

  29. A. M. Tritscher, G. C. Clark, C. Sewall, R. C. Sills, R. Maronpot, and G. W. Lucier (1995). Persistence of TCDD-induced hepatic cell proliferation and growth of enzyme altered foci after chronic exposure followed by cessation of treatment in DEN initiated female rats. Carcinogenesis 16:2807–2811.

    Google Scholar 

  30. R. Bannister, L. Biegel, D. Davis, B. Astroff, and S. Safe (1989). 6-Methyl-1,3,8-trichlorodibenzofuran (MCDF) as a 2,3,7,8-tetrachlorodibenzo-p-dioxin antagonist in C57BL/6 mice. Toxicology 54:139–150.

    Google Scholar 

  31. C. Yao and S. Safe (1989). 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced porphyria in genetically inbred mice: Partial antagonism and mechanistic studies. Toxicol. Appl. Pharmacol. 100:208–216.

    Google Scholar 

  32. B. Astroff, T. Zacharewski, S. Safe, M. P. Arlotto, A. Parkinson, P. Thomas, and W. Levin (1988). 6-Methyl-1,3,8-trichlorodibenzofuran as a 2,3,7,8-tetrachlorodibenzo-p-dioxin antagonist: Inhibition of the induction of rat cytochrome P-450 isozymes and related monooxygenase activities. Mol. Pharmacol. 33:231–236.

    Google Scholar 

  33. B. Astroff and S. Safe (1991). 6-Alkyl-1,3,8-trichlorodibenzofurans as antiestrogens in female Sprague-Dawley rats. Toxicology 69:187–197.

    Google Scholar 

  34. T. Zacharewski, M. Harris, L. Biegel, V. Morrison, M. Merchant, and S. Safe (1992). 6-Methyl-1,3,8-trichlorodibenzofuran (MCDF) as an antiestrogen in human and rodent cancer cell lines: Evidence for the role of the Ah receptor. Toxicol. Appl. Pharmacol. 13:311–318.

    Google Scholar 

  35. R. Dickerson, L. Howie-Keller, and S. Safe (1995). Alkyl polychlorinated dibenzofurans and related compounds as anties trogens in the female rat uterus: Structure-activity studies. Toxicol. Appl. Pharmacol. 135:287–298.

    Google Scholar 

  36. G. Sun and S. Safe (1997). Antiestrogenic activities of alternate substituted polychlorinated dibenzofurans in MCF-7 human breast cancer cells. Cancer Chemotherapy Pharmacol. 40:239–244.

    Google Scholar 

  37. A. McDougal, C. Wilson, and S. Safe (1997). Inhibition of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumor growth by aryl hydrocarbon receptor agonists. Cancer Lett. 120:53–63.

    Google Scholar 

  38. L. F. Bjeldanes, J. Y. Kim, K. R. Grose, J. C. Bartholomew, and C. A. Bradfield (1991). Aromatic hydrocarbon responsivenessreceptor agonists generated from indole-3-carbinol in vitro and in vivo—comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc. Natl. Acad. Sci. U.S.A. 88:9543–9547.

    Google Scholar 

  39. I. Chen, S. Safe, and L. Bjeldanes (1996). Indole-3-carbinol and diindolylmethane as aryl hydrocarbon (Ah) receptor agonists and antagonists in T47D human breast cancer cells. Biochem. Pharmacol. 51:1069–1076.

    Google Scholar 

  40. I. Chen, A. McDougal, F. Wang, and S. Safe (1998). Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane. Carcinogenesis 19:1631–1639.

    Google Scholar 

  41. S. M. Hyder, C. Chiappetta, L. Murthy, and G. M. Stancel (1997). Selective inhibition of estrogen-regulated gene expression in vivo by the pure antiestrogen ICI 182,780. Cancer Res. 57:2547–2549.

    Google Scholar 

  42. J. Z. Yang and W. G. Foster (1997). Continuous exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin inhibits the growth of surgically induced endometriosis in the ovariectomized mouse treated with high dose estradiol. Toxicol. Ind. Health 13:15–25.

    Google Scholar 

  43. G. W. Lucier, A. Tritscher, T. Goldsworthy, J. Foley, G. Clark, J. Goldstein, and R. Maronpot (1991). Ovarian hormones enhance 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated increases in cell proliferation and preneoplastic foci in a two-stage model for rat hepatocarcinogenesis. Cancer Res. 51:1391–1397.

    Google Scholar 

  44. A. M. Tritscher, A. M. Seacat, J. D. Yager, J. D. Groopman, B. D. Miller, D. Bell, T. R. Sutter, and G. W. Lucier (1996). Increased oxidativeDNAdamage in livers of 2,3,7,8-tetrachlorodibenzo-p-dioxin treated intact but not ovariectomized rats. Cancer Lett. 98:219–225.

    Google Scholar 

  45. N. M. Brown, P. A. Manzolillo, J. X. Zhang, J. Wang, and C. A. Lamartiniere (1998). Prenatal TCDD and predisposition to mammary cancer in the rat. Carcinogenesis 19:1623–1629.

    Google Scholar 

  46. J. F. Gierthy, D. W. Lincoln, M. B. Gillespie, J. I. Seeger, H. L. Martinez, H. W. Dickerman, and S. A. Kumar (1987). Suppression of estrogen-regulated extracellular plasminogen activator activity of MCF-7 cells by 2,3,7,8-tetrachlorodibenzop-dioxin. Cancer Res. 47:6198–6203.

    Google Scholar 

  47. J. F. Gierthy and D. W. Lincoln. (1988). Inhibition of postcon-fluent focus production in cultures of MCF-7 breast cancer cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Breast Cancer Res. Treat. 12:227–233.

    Google Scholar 

  48. L. Biegel and S. Safe (1990). Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on cell growth and the secretion of the estrogen-induced 34-, 52-and 160-kDa proteins in human breast cancer cells. J. Steroid Biochem. Mol. Biol. 37:725–732.

    Google Scholar 

  49. V. Krishnan and S. Safe (1993). Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) as antiestrogens in MCF-7 human breast cancer cells: Quantitative structure-activity relationships. Toxicol. Appl. Pharmacol. 120:55–61.

    Google Scholar 

  50. V. Krishnan, T. R. Narasimhan, and S. Safe (1992). Development of gel staining techniques for detecting the secretion of procathepsin D (52-kDa protein) in MCF-7 human breast cancer cells. Anal. Biochem. 204:137–142.

    Google Scholar 

  51. V. Krishnan, W. Porter, M. Santostefano, X. Wang, and S. Safe (1995). Molecular mechanism of inhibition of estrogeninduced cathepsin D gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in MCF-7 cells. Mol. Cell. Biol. 15:6710–6719.

    Google Scholar 

  52. M. Moore, T. R. Narasimhan, X. Wang, V. Krishnan, S. Safe, H. J. Williams, and A. I. Scott (1993). Interaction of 2,3,7,8-tetrachlorodibenzo-p-dioxin, 12-O-tetradecanoylphorbol-13-acetate (TPA) and 17β-estradiol in MCF-7 human breast cancer cells. J. Steroid Biochem. Mol. Biol. 44:251–261.

    Google Scholar 

  53. T. R. Narasimhan, S. Safe, H. J. Williams, and A. I. Scott (1991). Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on 17β-estradiol-induced glucose metabolism in MCF-7 human breast cancer cells: 13C-nuclear magnetic resonance studies. Mol. Pharmacol. 40:1029–1035.

    Google Scholar 

  54. T. R. Zacharewski, K. L. Bondy, P. McDonell, and Z. F. Wu (1994). Antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on 17β-estradiol-induced pS2 expression. Cancer Res. 54:2707–2713.

    Google Scholar 

  55. Y.-F. Lu, G. Sun, X. Wang, and S. Safe (1996). Inhibition of prolactin receptor gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin in MCF-7 human breast cancer cells. Arch. Biochem. Biophys. 332:35–40.

    Google Scholar 

  56. W. Wang, R. Smith, and S. Safe (1998). Aryl hydrocarbon receptor-mediated antiestrogenicity in MCF-7 cells: Modulation of hormone-induced cell cycle enzymes. Arch. Biochem. Biophys. 356:239–248.

    Google Scholar 

  57. M. Harris, T. Zacharewski, and S. Safe (1990). Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds on the occupied nuclear estrogen receptor in MCF-7 human breast cancer cells. Cancer Res. 50:3579–3584.

    Google Scholar 

  58. X. Wang, W. Porter, V. Krishnan, T. R. Narasimhan, and S. Safe (1993). Mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated decrease of the nuclear estrogen receptor in MCF-7 human breast cancer cells. Mol. Cell. Endocrinol. 96:159–166.

    Google Scholar 

  59. M. Moore, X. Wang, Y.-F. Lu, M. Wormke, A. Craig, J. Gerlach, R. Burghardt, and S. Safe (1994). Benzo[a]pyrene resistant (BaPR) human breast cancer cells: A unique aryl hydrocarbon (Ah)-nonresponsive clone. J. Biol. Chem. 269:11751–11759.

    Google Scholar 

  60. I. Kharat and F. Saatcioglu (1996). Antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin are mediated by direct transcriptional interference with the liganded estrogen receptor. J. Biol. Chem. 271:10533–10537.

    Google Scholar 

  61. C. M. Klinge, K. Kaur, and H. I. Swanson (2000). The aryl hydrocarbon receptor interacts with estrogen receptor α and orphan receptors COUP-TFI and ERRα1. Arch. Biochem. Biophys. 373:163–174.

    Google Scholar 

  62. Z. Nawaz, D. M. Lonard, A. P. Dennis, C. L. Smith, and B. W. O'Malley (1999). Proteasome-dependent degradation of the human estrogen receptor. Proc. Natl. Acad. Sci. U.S.A. 96:1858–1862.

    Google Scholar 

  63. N. A. Davarinos and R. S. Pollenz (1999). Aryl hydrocarbon receptor imported into the nucleus following ligand binding is rapidly degraded via the cytosplasmic proteasome following nuclear export. J. Biol. Chem. 274:28708–28715.

    Google Scholar 

  64. I. Chen, T. Hsieh, T. Thomas, and S. Safe (2000). Mechanisms of inhibitory aryl hydrocarbon receptor-estrogen receptor crosstalk in MCF-7 breast cancer cells: Identification of genes downregulated by AhR agonists using suppression subtractive hybridization. Gene (in press).

  65. W. Porter, B. Saville, D. Hoivik, and S. Safe (1997). Functional synergy between the transcription factor Sp1 and the estrogen receptor. Mol. Endocrinol. 11:1569–1580.

    Google Scholar 

  66. R. Duan, W. Porter, and S. Safe (1998). Estrogen-induced cfos protooncogene expression in MCF-7 human breast cancer cells: role of estrogen receptor Sp1 complex formation. Endocrinology 139:1981–1990.

    Google Scholar 

  67. F. Wang, D. Hoivik, R. Pollenz, and S. Safe (1998). Functional and physical interactions between the estrogen receptor-Sp1 and the nuclear aryl hydrocarbon receptor complexes. Nucleic Acids Res. 26:3044–3052.

    Google Scholar 

  68. G. Sun, W. Porter, and S. Safe (1998). Estrogen-induced retinoic acid receptor α1 gene expression: Role of estrogen receptor-Sp1 complex. Mol. Endocrinol. 12:882–890.

    Google Scholar 

  69. W. Xie, R. Duan, and S. Safe (1999). Estrogen induces adenosine deaminase gene expression in MCF-7 human breast cancer cells: Role of estrogen receptor-Sp1 interactions. Endocrinology 140:219–227.

    Google Scholar 

  70. C. Qin, P. Singh, and S. Safe (1999). Transcriptional activation of insulin-like growth factor binding protein 4 by 17β-estradiol in MCF-7 cells: Role of estrogen receptor-Sp1 complexes. Endocrinology 140:2501–2508.

    Google Scholar 

  71. W. Wang, L. Dong, B. Saville, and S. Safe (1999). Transcriptional activation of E2F1 gene expression by 17β-estradiol in MCF-7 cells is regulated by NF-Y-Sp1/estrogen receptor interactions. Mol. Endocrinol. 13:1373–1387.

    Google Scholar 

  72. B. Gillesby, M. Santostefano, W. Porter, Z. F. Wu, S. Safe, and T. Zacharewski (1997). Identification of a motif within the 5'-regulatory region on pS2 which is responsible for Ap1 binding and TCDD-mediated suppression. Biochemistry 36:6080–6089.

    Google Scholar 

  73. A. D. Johnson (1995). The price of repression. Cell 81:655–658.

    Google Scholar 

  74. R. Duan, W. Porter, I. Samudio, C. Vyhlidal, M. Kladde, and S. Safe (1999). Transcriptional activation of c-fos protooncogene by 17β-estradiol: Mechanism of aryl hydrocarbon receptor-mediated inhibition. Mol. Endocrinol. 13:1511–1521.

    Google Scholar 

  75. K. Ramamoorthy, M. S. Gupta, G. Sun, A. McDougal, and S. H. Safe (1999). 3,3',4,,4'-Tetrachlorobiphenyl exhibits antiestrogenic and antitumorigenic activity in the rodent uterus and mammary and in human breast cancer cells. Carcinogenesis 20:115–123.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Safe, S., Wormke, M. & Samudio, I. Mechanisms of Inhibitory Aryl Hydrocarbon Receptor-Estrogen Receptor Crosstalk in Human Breast Cancer Cells. J Mammary Gland Biol Neoplasia 5, 295–306 (2000). https://doi.org/10.1023/A:1009550912337

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1009550912337

Navigation