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Laboratory of Genetics and Biochemistry, San Paolo University Hospital, School of Medicine, University of Milan, 20142 Milan, Italy [S. M.S., E. S., G. S., R. G., N. S.]; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland 21231-1000 [M. R., R. P., N. S.]; Department of Oncology, Biology and Genetics, University of Genoa, 16132 Italy [S. T.]; and National Institute for Cancer Research, 16132 Genoa, Italy [S. T., G. N.]
Loss of expression of retinoic acid receptor ß2 (RARß2), a potent tumor suppressor gene, is commonly observed during breast carcinogenesis. RARß2 silencing can be traced to epigenetic chromatin changes affecting the RARß P2 promoter. Here we show that retinoic acid therapy fails to induce RARß2 in primary breast tumors, which carry a methylated RARß P2 promoter. DNA methylation leads to repressive chromatin deacetylation at RARß P2. By inducing an appropriate level of histone reacetylation at RARß P2 we could reactivate endogenous RARß2 transcription from unmethylated as well as methylated RARß P2 in breast cancer cell lines and xenograft tumors, and obtain significant growth inhibition both in vitro and in vivo. This study may have translational implications for breast cancer and other cancers carrying an epigenetically silenced RARß P2 promoter.
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