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Molecular Cancer Therapeutics
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Article

Valproic acid, in combination with all-trans retinoic acid and 5-aza-2′-deoxycytidine, restores expression of silenced RARβ2 in breast cancer cells

Nigel P. Mongan and Lorraine J. Gudas
Nigel P. Mongan
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Lorraine J. Gudas
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DOI: 10.1158/1535-7163.MCT-04-0079 Published March 2005
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Abstract

Epigenetic silencing of tumor suppressor genes has been established as an important process of carcinogenesis. The retinoic acid (RA) receptor β2 (RARβ2) gene is one such tumor suppressor gene often silenced during carcinogenesis. The combined use of histone deacetylase and DNA methyltransferase inhibitors has been shown to reverse the epigenetic silencing of numerous growth regulatory genes. Valproic acid (VPA), which has long been used in the treatment of epilepsy, was shown recently to be an effective histone deacetylase inhibitor that can induce differentiation of neoplastically transformed cells. In this study, we show for the first time that VPA, in combination with RA and the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (Aza-dC), can overcome the epigenetic barriers to transcription of a prototypical silenced tumor suppressor gene, RARβ2, in human breast cancer cells. Chromatin immunoprecipitation assays show that the combination of VPA, RA, and Aza-dC increases histone acetylation at the silenced RARβ2 promoter of MCF-7 breast cancer cells. Furthermore, reverse transcription-PCR analyses reveal cell type–specific effects in the actions of VPA on RARβ2 expression in cultured human breast cancer cells. Finally, we show that VPA, in combination with RA and Aza-dC, inhibits the proliferation of both estrogen receptor α-positive (MCF-7) and estrogen receptor α-negative (MDA-MB-231) breast cancer cell lines. These data suggest that VPA may ultimately be useful in combination therapies in the treatment of human breast cancers.

Keywords:
  • Chromatin immunoprecipitation
  • 5-aza-2′-deoxycytidine
  • HDAC inhibitor
  • breast cancer
  • retinoic acid receptor
  • tumor suppressor
  • valproic acid

Footnotes

  • Grant support: NIH grants R01DE10389 and R01CA77509 (L.J. Gudas) and AACR-Cancer Research Foundation of America postdoctoral fellowship (N.P. Mongan).

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted January 5, 2005.
    • Received March 22, 2004.
    • Revision received December 22, 2004.
  • American Association for Cancer Research
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Molecular Cancer Therapeutics: 4 (3)
March 2005
Volume 4, Issue 3
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Valproic acid, in combination with all-trans retinoic acid and 5-aza-2′-deoxycytidine, restores expression of silenced RARβ2 in breast cancer cells
Nigel P. Mongan and Lorraine J. Gudas
Mol Cancer Ther March 1 2005 (4) (3) 477-486; DOI: 10.1158/1535-7163.MCT-04-0079

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Valproic acid, in combination with all-trans retinoic acid and 5-aza-2′-deoxycytidine, restores expression of silenced RARβ2 in breast cancer cells
Nigel P. Mongan and Lorraine J. Gudas
Mol Cancer Ther March 1 2005 (4) (3) 477-486; DOI: 10.1158/1535-7163.MCT-04-0079
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Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

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