Evidence of epigenetic changes affecting the chromatin state of the retinoic acid receptor β2 promoter in breast cancer cells

Silvia M. Sirchia, Anne T. Ferguson, Elena Sironi, Smitha Subramanyan, Rosaria Orlandi, Saraswati Sukumar, Nicoletta Sacchi

Research output: Contribution to journalArticle

Abstract

Retinoic acid (RA)-resistance in breast cancer cells has been associated with irreversible loss of retinoic acid receptor β, RARβ, gene expression. Search of the causes affecting RARβ gene activity has been oriented at identifying possible differences either at the level of one of the RARβ promoters, RARβ2, or at regulatory factors. We hypothesized that loss of RARβ2 activity occurs as a result of multiple factors, including epigenetic modifications, which can pattern RARβ2 chromatin state. Using methylation-specific PCR, we found hypermethylation at RARβ2 in a significant proportion of both breast cancer cell lines and primary breast tumors. Treatment of cells with a methylated RARβ2 promoter, by means of the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR), led to demethylation within RARβ2 and expression of RARβ indicating that DNA methylation is at least one factor, contributing to RARβ inactivity. However, identically methylated promoters can differentially respond to RA, suggesting that RARβ2 activity may be associated to different repressive chromatin states. This supposition is supported by the finding that the more stable repressive RARβ2 state in the RA-resistant MDA-MB-231 cell line can be alleviated by the HDAC inhibitor, trichostatin A (TSA), with restoration of RA-induced RARβ transcription. Thus, chromatin-remodeling drugs might provide a strategy to restore RARβ activity, and help to overcome the hurdle of RA-resistance in breast cancer.

Original languageEnglish
Pages (from-to)1556-1563
Number of pages8
JournalOncogene
Volume19
Issue number12
Publication statusPublished - Mar 16 2000

Keywords

  • Breast cancer
  • Chromatin remodeling
  • DNA methylation
  • Retinoic acid receptor (RAR) β

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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  • Cite this

    Sirchia, S. M., Ferguson, A. T., Sironi, E., Subramanyan, S., Orlandi, R., Sukumar, S., & Sacchi, N. (2000). Evidence of epigenetic changes affecting the chromatin state of the retinoic acid receptor β2 promoter in breast cancer cells. Oncogene, 19(12), 1556-1563.