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Molecular Medicine

, Volume 13, Issue 1–2, pp 69–78 | Cite as

Interplay of Genes Regulated by Estrogen and Diindolylmethane in Breast Cancer Cell Lines

  • Laura Mulvey
  • Alamelu Chandrasekaran
  • Kai Liu
  • Sarah Lombardi
  • Xue-Ping Wang
  • Karen J. Auborn
  • Leslie Goodwin
Research Article

Abstract

Diindolylmethane (DIM), a biologically active congener of indole-3-carbinol (I3C) derived from cruciferous vegetables, is a promising agent for the prevention of estrogen-sensitive cancers. Both DIM and estrogen affect transcription of genes by binding receptors, such as aryl hydrocarbon receptor (AhR) or estrogen receptors (ER). Gene regulation by DIM and estradiol (E2) can be very complex. While DIM typically binds the AhR, this complex can directly associate with the ER, recruit co-activators that bind to estrogen-responsive promoters, and activate transcription. Alternately, DIM can bind the ER directly. In this study, we have analyzed gene expression using microarray profiling and quantitative real time-polymerase chain reaction in MCF7 breast cancer cells treated with E2 (1 nM) or DIM (25 µM) alone or in combination for 16 h. The interplay of E2 and DIM was reflected in the expression of a subset of genes (<90) in which the combination of E2 and DIM acted either additively or antagonistically to alter gene expression.

Notes

Acknowledgments

Laura Mulvey and Alamelu Chandrasekaran contributed equally to this work. This work was supported by RO1-CA733850 to KJA from the National Institutes of Health.

References

  1. 1.
    Ge X, Fares FA, Yannai S. 1999. Induction of apoptosis in MCF-7 cells by indole-3-carbinol is independent of p53 and bax. Anticancer Res. 19:3199–3203.PubMedGoogle Scholar
  2. 2.
    Chen DZ, Qi M, Auborn KJ, Carter TH. 2001. Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cells and in murine HPV-16 transgenic preneoplastic cervical epithelium. J. Nutr. 131:3294–3302.CrossRefGoogle Scholar
  3. 3.
    Bjeldanes LF, Kim JY, Grose KR, Bartholomew JC, Bradfield CA. 1991. Aromatic hydrocarbon responsiveness-receptor 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.CrossRefGoogle Scholar
  4. 4.
    Edwards DP, Adams DJ, McGuire WI. 1981. Estrogen regulation of growth and specific protein synthesis in human breast cancer cells in tissue culture. Adv. Exp. Biol. 138:133–149.CrossRefGoogle Scholar
  5. 5.
    Newfield L, Bradlow HL, Sepkovic DW, Auborn K. 1998. Estrogen metabolism and the malignant potential of human papillomavirus immortalized keratinocytes. Exp. Biol. Med. 217:322–326.CrossRefGoogle Scholar
  6. 6.
    Prall OWJ, Sarcevic B, Musgrove EA, Watts CK, Sutherland RL. 1997. Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J. Biol. Chem. 272:10882–10894.CrossRefGoogle Scholar
  7. 7.
    Lobenhofer EK, Lee Bennet P, Cable L, Li L, Bushel PR, Afshara CA. 2002. Regulation of DNA replication fork genes by 17b-estradiol. Mol. Endocrinol. 16:1215–1229.PubMedGoogle Scholar
  8. 8.
    Perillo B, Sasso A, Abbondanza C, Palumbo G. 2000. 17β-estradiol inhibits apoptosis in MCF-7 cells, inducing bcl-2 expression via 2 estrogen-responsive elements present in the coding sequence. Mol. Cell. Biol. 8:2890–2901.CrossRefGoogle Scholar
  9. 9.
    Jin L et al. 1999. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res. 59:3991–3997.PubMedGoogle Scholar
  10. 10.
    Bell MC et al. 2000. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol. Oncol. 78:123–129.CrossRefGoogle Scholar
  11. 11.
    Bradlow HL, Michnovicz JJ, Telang NT, Osborne MP. 1991. Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice. Carcinogenesis 12:1571–1574.CrossRefGoogle Scholar
  12. 12.
    Kojima T, Tanaka T, Mori H. 1994. Chemoprevention of spontaneous endometrial cancer in female donyru rats by indole-3-carbinol. Cancer Res. 54:1446–1449.PubMedGoogle Scholar
  13. 13.
    Chen D-Z, Carter TH, Auborn KJ. 2004. Apoptosis in cervical cancer cells: Implications for adjunct anti-estrogen therapy for cervical cancer. Anticancer Res. 24:2649–2656.PubMedGoogle Scholar
  14. 14.
    Chen I, Safe S, Bjeldanes L. 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.CrossRefGoogle Scholar
  15. 15.
    Bradlow HL, Telang NT, Sepkovik DW, Osborn MP. 1996. 2-Hydroxyestrone: the “good” estrogen. J. Endrocrinol. 150:S259–265.Google Scholar
  16. 16.
    LaVallee TM et al. 2002. 2-Methoxyestradiol inhibits proliferation and induces apoptosis independently of estrogen receptors a and beta. Cancer Res. 62:3691–3697.PubMedGoogle Scholar
  17. 17.
    Meng Q et al. 2000. Suppression of breast cancer invasion and migration by indole-3-carbinol: associated with up-regulation of BRCA1 and E-cadherin/catenin complexes. J. Mol. Med. 78:155–165.CrossRefGoogle Scholar
  18. 18.
    Fan S et al. 1999. BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science 284:1354–1356.CrossRefGoogle Scholar
  19. 19.
    Liu H, Wormke M, Safe SH, Bjeldanes LF. 1994. Indolo[3,2-b]carbazole: a dietary-derived factor that exhibits both antiestrogenic and estrogenic activity. J. Natl. Cancer Inst. 86:1758–1765.CrossRefGoogle Scholar
  20. 20.
    Auborn KJ et al. 2003. Indole-3-carbinol is a negative regulator of estrogen. J. Nutr. 133:2470s–2475s.CrossRefGoogle Scholar
  21. 21.
    Evans RM. 1998. The steroid and thyroid hormone receptor superfamily. Science 240:889–895.CrossRefGoogle Scholar
  22. 22.
    Katzenellenobogen BS. 1996. Estrogen receptors: bioactivities and interactions with cell signaling pathways. Biol. Reprod. 54:287–293.CrossRefGoogle Scholar
  23. 23.
    Safe S, Krishnan V. 1995. Cellular and molecular biology of aryl hydrocarbon (Ah) receptor-mediated gene expression. Arch. Toxicol. Suppl. 17:99–115.CrossRefGoogle Scholar
  24. 24.
    Riby J, Chang G, Firestone G, Bjeldanes L. 2000. Ligand-independent activation of estrogen receptor function by 3,3′ diindolylmethane in human breast cancer cells. Biochem. Pharmacol. 60:167–177.CrossRefGoogle Scholar
  25. 25.
    Ohtake F et al. 2003. Modulation of oestrogen receptor signaling by association with the activated dioxin receptor. Nature 423:545–550.CrossRefGoogle Scholar
  26. 26.
    Chen I, Hsieh T, Thomas T, Safe S. 2001. Identification of estrogen-induced genes downregulated by AhR agonists in MCF-7 breast cancer cells using suppression subtractive hybridization. Gene 262:207–214.CrossRefGoogle Scholar
  27. 27.
    Chen I, McDougal A, Wang F, Safe S. 1998. Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane. Carcinogenisis 19:1631–1639.CrossRefGoogle Scholar
  28. 28.
    Chang X et al. 2005. 3,3′-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice. Carcinogenesis 26:771–778.CrossRefGoogle Scholar
  29. 29.
    Terry P, Wolk A, Persson I, Magnusson C. 2001. Brassica vegetables and breast cancer risk. J. Am. Med. Assoc. 285:2975–2977.CrossRefGoogle Scholar
  30. 30.
    Russo J, Hasan Lareef M, Balogh G, Russo IH. 2003. Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells. Steroid Biochem. Mol. Biol. 87:1–25.CrossRefGoogle Scholar
  31. 31.
    Rogan EG et al. 2003. Relative imbalances in estrogen metabolism and conjugation in breast tissue of women with carcinoma: potential bio-markers of susceptibility to cancer. Carcinogenesis 24:697–702.CrossRefGoogle Scholar
  32. 32.
    Jin L et al. 1999. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res. 59:3991–3997.PubMedGoogle Scholar
  33. 33.
    Lahita RG, Bradlow HL, Kunkel HG, Fishman J. 1979. Alterations of estrogen metabolism in systemic lupus erythematosus. Arthritis Rheum. 22:1195–1198.CrossRefGoogle Scholar
  34. 34.
    Auborn KJ et al. 2003. Lifespan is prolonged in autoimmune-prone (NZB/NZW) F1 mice fed a diet supplemented with indole-3-carbinol. J. Nutr. 133:3610–3613.CrossRefGoogle Scholar
  35. 35.
    Penning TM et al. 2000. Human 3 α-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Biochem J. 351:67–77.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Lewis MJ, Wiebe JP, Heathcote JG. 2004. Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma. BMC Cancer 4:27–38.CrossRefGoogle Scholar
  37. 37.
    Phan RT, Dalla-Favera R. 2004. The BCL6 proto-oncogene suppresses p53 expression in germinal-center B cells. Nature 432:635–639.CrossRefGoogle Scholar
  38. 38.
    Yeh PY et al 2006. A pathway for tumor necrosis factor-a-induced Bcl10 nuclear translocation. J. Biol. Chem. 281:167–175.CrossRefGoogle Scholar
  39. 39.
    Bouzahzah B et al. 2001. Rho family GTPases regulate mammary epithelium cell growth and metastasis through distinguishable pathways. Mol. Med. 7:816–830.CrossRefGoogle Scholar
  40. 40.
    Baugher PJ, Krishnamoorthy L, Price JE, Dharmawardhane SF. 2005. Rac1 and Rac3 isoform activation is involved in the invasive and metastatic phenotype of human breast cancer cells. Breast Cancer Res. 7:R965–R974.CrossRefGoogle Scholar
  41. 41.
    Liang Z et al. 2005. Silencing of CXCR4 blocks breast cancer metastasis. Cancer Res. 65:967–971.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Kang H et al. 2005. Stromal cell derived factor-1: its influence on invasiveness and migration of breast cancer cells in vitro, and its association with prognosis and survival in human breast cancer. Breast Cancer Res. 7:R402–R410.CrossRefGoogle Scholar
  43. 43.
    Li YM et al. 2004. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell 6:459–430.CrossRefGoogle Scholar
  44. 44.
    Collert MA, Struhl K. 1994. NOT1(CDC39), NOT2(CDC36), NOT3, and NOT4 encode a global-negative regulator of transcription that differentially affects TATA-element utilization. Genes Dev. 8:525–537.CrossRefGoogle Scholar
  45. 45.
    Cheng L, Wing HW. (2001a). Model-based analysis of oligonucleotide arrays: Expression index computation and outlier detection. Proc. Natl. Acad. Sci. 98:31–36.CrossRefGoogle Scholar
  46. 46.
    Cheng L, Wing HW. (2001b). Model-based analysis of oligonucleotide arrays: model validation, design issues and standard error application. Genome Biol. 2:research0032.1–0032.11Google Scholar
  47. 47.
    Nebert DW et al. 2000. Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response cell cycle control and apoptosis. Biochem. Pharmacol. 59:65–85.CrossRefGoogle Scholar
  48. 48.
    Reymann S, Borlak J. 2006. Transcriptome profiling of human hepatocytes treated with Aroclor 1254 reveals transcription factor regulatory networks and clusters of regulated genes. BMC Genomics 7:217–235.CrossRefGoogle Scholar
  49. 49.
    Liu S et al. 2006. Aryl hydrocarbon receptor agonists directly activate estrogen receptor α in MCF-7 breast cancer cells. Biol. Chem. 387:1209–1213.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2007

Authors and Affiliations

  • Laura Mulvey
    • 1
  • Alamelu Chandrasekaran
    • 1
  • Kai Liu
    • 1
  • Sarah Lombardi
    • 1
  • Xue-Ping Wang
    • 1
  • Karen J. Auborn
    • 1
    • 2
    • 3
  • Leslie Goodwin
    • 1
  1. 1.Feinstein Institute for Medical ResearchManhassetUSA
  2. 2.Department of Otolaryngology, Long Island Jewish Medical CenterThe Long Island Campus of Albert Einstein College of MedicineNew Hyde ParkUSA
  3. 3.Department of Microbiology and ImmunologyAlbert Einstein College of MedicineBronxUSA

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