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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)177-186
Number of pages10
JournalBreast Cancer Research and Treatment
Volume81
Issue number3
DOIs
StatePublished - Oct 1 2003

Keywords

  • 5-aza-2′-deoxycytidine
  • Breast cancer
  • DNA methylation
  • Estrogen receptor α
  • Histone acetylation
  • Scriptaid

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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