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

Oncogene volume 19, pages 1556–1563 (2000)Cite this article

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.

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Acknowledgements

We thank Drs WEC Bradley (Montreal) and X-Q Zhang (La Jolla) for initial helpful discussions on the idea behind this work and reagents and Dr A Hoogeveen for critical suggestions; Dr M Stampfer for the gift of the HMEC strains; Dr A de Klein for providing DNA from breast tumors. Funding for this work were provided by Associazione Italiana Ricerca sul Cancro (AIRC) and by BC980803 (USA) to N Sacchi.

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Authors and Affiliations

  1. Laboratory of Human Genetics, Hospital San Paolo, University of Milan, Milan, Italy

    Silvia M Sirchia

  2. Department of Biology, University of Milan, Milan, Italy

    Silvia M Sirchia, Elena Sironi & Nicoletta Sacchi

  3. Breast Cancer Program, Oncology Center, Johns Hopkins University, Baltimore, Maryland, USA

    Anne T Ferguson, Smitha Subramanyan & Saraswati Sukumar

  4. Instituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy

    Rosaria Orlandi

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  1. Silvia M Sirchia
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  2. Anne T Ferguson
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Sirchia, S., Ferguson, A., Sironi, E. et al. Evidence of epigenetic changes affecting the chromatin state of the retinoic acid receptor β2 promoter in breast cancer cells. Oncogene 19, 1556–1563 (2000). https://doi.org/10.1038/sj.onc.1203456

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