Breast Cancer Research and Treatment

, Volume 81, Issue 3, pp 177–186 | Cite as

A Novel Histone Deacetylase Inhibitor, Scriptaid, Enhances Expression of Functional Estrogen Receptor α (ER) in ER negative human breast cancer cells in combination with 5-aza 2′-deoxycytidine

  • Judith Clancy Keen
  • Lan Yan
  • Kelly M. Mack
  • Catherine Pettit
  • Dawn Smith
  • Dipali Sharma
  • Nancy E. Davidson
Article

Abstract

Epigenetic mechanisms, such as DNA methylation and histone deacetylation, may play a role in loss of estrogen receptor α (ER) expression in ER negative human breast cancer cells. Our previous studies showed that pharmacologic inhibition of these mechanisms using the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (AZA), and the histone deacetylase (HDAC) inhibitor, Trichostatin A (TSA), resulted in expression of functional ER mRNA and protein. Therefore, we sought to characterize the effects of a recently described HDAC inhibitor, Scriptaid, on cell growth and ER expression and function in ER negative human breast cancer cell lines. Scriptaid treatment of three ER negative cell lines, MDA-MB-231, MDA-MB-435 and Hs578t, resulted in significant growth inhibition and increased acetylation of H3 and H4 histone tails. Quantitative Real Time PCR showed 2000–20,000-fold increase of ER mRNA transcript in all three cell lines after 48 h of Scriptaid treatment. Further, dose dependent re-expression of an estrogen responsive gene, the progesterone receptor (PR), indicated that induced ER is functional. As seen with TSA and AZA, Scriptaid and AZA co-treatment was more effective in inducing ER than Scriptaid or AZA alone. In vivo analysis using a xenograft mouse model bearing MDA-MB-231 tumors showed decreased tumor growth following Scriptaid or TSA treatment. Our results indicate that the novel HDAC inhibitor, Scriptaid, inhibits tumor growth in vitro and in vivo and, in conjunction with AZA, acts to re-express functional ER. These data suggest that Scriptaid or related HDAC inhibitors are candidates for further study in breast cancer.

5-aza-2′-deoxycytidine breast cancer DNA methylation estrogen receptor α histone acetylation Scriptaid 

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References

  1. 1.
    Keen JC, Davidson NE: The biology of breast carcinoma. Cancer 97: 825–833, 2003Google Scholar
  2. 2.
    Asch BB, Barcellos-Hoff MH: Epigenetics and breast cancer. J Mammary Gland Biol Neoplasia 6: 151–152, 2001Google Scholar
  3. 3.
    Iwase H, Omoto Y, Iwata H, Toyama T, Hara Y, Ando Y, Ito Y, Fujii Y, Kobayashi S: DNA methylation analysis at distal and proximal promoter regions of the oestrogen receptor gene in breast cancers. Br J Cancer 80: 1982–1986, 1999Google Scholar
  4. 4.
    Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin, SB: Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 21: 103–107, 1999Google Scholar
  5. 5.
    Baylin S, Bestor TH: Altered methylation patterns in cancer cell genomes: cause or consequence? Cancer Cell 1: 299–305, 2002Google Scholar
  6. 6.
    Jones PA, Baylin SB: The fundamental role of epigenetic events in cancer. Nat Rev Genet 3: 415–428, 2002Google Scholar
  7. 7.
    Cheung W, Briggs S, Allis C: Acetylation and chromosomal functions. Curr Opin Cell Biol 12: 326–333, 2000Google Scholar
  8. 8.
    Bird A: Methylation talk between histones and DNA. Science 294: 2113–2115, 2001Google Scholar
  9. 9.
    Bird A, Wolffe A: Methylation-induced repression-belts, braces, and chromatin. Cell 99: 451–454, 1999Google Scholar
  10. 10.
    Bovenzi V, Momparler R: Antineoplastic action of 5-aza-2_-deoxycytidine and histone deacetylase inhibitor and their effect on the expression of retinoic acid receptor β and estrogen receptor α genes in breast carcinoma cells. Cancer Chemother Pharmacol 48: 71–76, 2001Google Scholar
  11. 11.
    Zhu WG, Otterson GA: The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Curr Med Chem Anti-Canc Agents 3: 187–199, 2003Google Scholar
  12. 12.
    Hebbes TR, Thorne AW, Crane-Robinson C: A direct link between core histone acetylation and transcriptionally active chromatin. Embo J 7: 1395–1402, 1988Google Scholar
  13. 13.
    Thaiagalingan S, Cheng K-H, Lee HJ, Mineva N, Thaiagalingan A, Ponte J: Histone deacetylases: unique players in shaping the epigenetic histone code. Ann NY Acad Sci 983: 84–100, 2003Google Scholar
  14. 14.
    Ferguson AT, Lapidus R, Baylin S, Davidson NE: Demethylation of the estrogen receptor gene in estrogen receptornegative breast cancer cells can reactivate estrogen receptor gene expression. Cancer Res 55: 2279–2283, 1995Google Scholar
  15. 15.
    Ottaviano Y, Issa J, Parl F, Smith H, Baylin S, Davidson N: Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res 54: 2552–2555, 1994Google Scholar
  16. 16.
    Yang X, Ferguson AT, Nass SJ, Phillips DL, Butash KA, Wang SM, Herman JG, Davidson NE: Transcriptional activation of estrogen receptor α in human breast cancer cells by histone deacetylase inhibition. Cancer Res 60: 6890–6894, 2000Google Scholar
  17. 17.
    Yang X, Phillips DL, Ferguson AT, Nelson WG, Herman JG, Davidson NE: Synergistic activation of functional estrogen receptor (ER)-α by DNA methyltransferase and histone deacetylase inhibition in human ER-α-negative breast cancer cells. Cancer Res 61: 7025–7029, 2001Google Scholar
  18. 18.
    Gore S, Carducci M: Modifying histones to tame cancer: clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors. Exp Opinion Invest Drugs 9: 2923–2934, 2000Google Scholar
  19. 19.
    Su GH, Sohn TA, Ryu B, Kern SE: A novel histone deacetylase inhibitor identified by high-throughput transcriptional screening of a compound library. Cancer Res 60: 3137–3142, 2000Google Scholar
  20. 20.
    Hahm H, Dunn V, Butash KA, Deveraux W, Woster P, Casero Jr R, Davidson NE: Combination of standard cytotoxic agents with polyamine analogues in the treatment of breast cancer cell lines. Clin Cancer Res 7: 391–399, 2001Google Scholar
  21. 21.
    Marks P, Rifkind R, Richon V, Breslow R, Miller T, Kelly W: Histone deacetylases and cancer: causes and therapies. Nature Rev: Cancer 1: 194–202, 2001Google Scholar
  22. 22.
    Vigushin D, Ali S, Pace P, Mirsaidi N, Ito K, Adcock I, Coombes R: Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin Cancer Res 7: 971–976, 2001Google Scholar
  23. 23.
    Iwase H: Molecular action of the estrogen receptor and hormone dependency in breast cancer. Breast Cancer 10: 89–96, 2003Google Scholar
  24. 24.
    Yan L, Yang X, Davidson NE: Role of DNA methylation and histone acetylation in steroid receptor expression in breast cancer.J Mammary Gland Biol Neoplasia 6: 83–192, 2001Google Scholar
  25. 25.
    Yan L, Nass SJ, Davidson NE: Effects of DMT 1 antisense oligonucleotide on steroid hormone expression in breast cancer cell lines. AACR 42: 844 (abstract #4556), 2001Google Scholar
  26. 26.
    Marks P, Richon V, Breslow R, Rifkind R: Histone deacetylase inhibitors as new cancer drugs. Curr Opin Oncol 13: 477–483, 2001Google Scholar
  27. 27.
    Butler LM, Agus DB, Scher HI, Higgins B, Rose A, Cordon-Cardo C, Thaler HT, Rifkind RA, Marks PA, Richon VM: Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res 60: 5165–5170, 2000Google Scholar
  28. 28.
    Vigushin DM, Ali S, Pace PE, Mirsaidi N, Ito K, Adcock I, Coombes RC: Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin Cancer Res 7: 971–976, 2001Google Scholar
  29. 29.
    Jenuwein T, Allis CD: Translating the histone code. Science 293: 1074–1080, 2001Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Judith Clancy Keen
    • 1
  • Lan Yan
    • 1
    • 2
  • Kelly M. Mack
    • 1
    • 3
  • Catherine Pettit
    • 1
  • Dawn Smith
    • 1
    • 4
  • Dipali Sharma
    • 1
  • Nancy E. Davidson
    • 1
  1. 1.The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA
  2. 2.Pfizer Inc.GrotonUSA
  3. 3.University of Maryland Eastern ShorePrincess AnneUSA
  4. 4.Centocor Inc.MalvernUSA

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