Modulation of Breast Tumor Cell Response to Retinoids by Histone Deacetylase Inhibitors

摘要

Retinoic acid (RA) resistance is a major hurdle of retinoid- differentiation therapy. One form of RA-resistance in breast cancer can be traced to loss of expression of the tumor suppressor RAR beta, due to epigenetic changes including DNA methylation and histone deacetylation in one of the RAR beta promoters. Epigenetic changes are reversible. By using histone deacetylase inhibitors (HDACT), including phenyl butyrate (PB) and Trichostatin A (TSA), we were able to revert epigenetic changes at RAR beta, restore RA sensitivity and induce endogenous RAR beta expression in RA-resistant breast cancer cells both in vivo and in vitro (Sirchia et al., Cancer Research, 62, 2455-2461, 2002). Our next goal is to evaluate whether we can improve reactivation of endogenous RAB beta. In the course of our preliminary studies we realized that the RA-resistant phenotype is associated with RAR beta promoter not only with a) heterogeneous DNA methylation/histone hypocetylation patterns but also b) different types and degree of histone modifications, including methylation at lysine 4 and 9 on Histone 3, acetylation at histone 3 and histone 4, and phosphorylation at serine 3 on Histone 3. It remains to be established whether these modifications can influence the efficiency of endogenous reactivation of RAR beta.