Loss of expression of retinoic acid receptor β2 (RARβ2), a potent tumor suppressor gene, is commonly observed during breast carcinogenesis. RARβ2 silencing can be traced to epigenetic chromatin changes affecting the RARβ P2 promoter. Here we show that retinoic acid therapy fails to induce RARβ2 in primary breast tumors, which carry a methylated RARβ P2 promoter. DNA methylation leads to repressive chromatin deacetylation at RARβ P2. By inducing an appropriate level of histone reacetylation at RARβ P2 we could reactivate endogenous RARβ2 transcription from unmethylated as well as methylated RARβ 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 RARβ P2 promoter.