Inactivation of genes that regulate cell proliferation and death is a critical part of the neoplastic process. Crucial genes like tumor suppressor genes can be inactivated via gene deletion, point mutation, or inhibition of transcription. One mechanism for transcriptional inhibition is methylation of cytosine-rich areas, termed CpG islands, in the 5' regulatory region of the target genes. Methylation in these islands can directly inhibit transcription or stabilize structural changes in chromatin that do not allow transcription and can be modified through inhibition of the enzyme, DNA methyltransferase. The role of histone acetylation as a mechanism to alter chromatin structure and gene transcription has also been recognized. This is modified by the actions of histone acetyltransferases and deacetylases. As DNA methylation and histone acetylation are reversible processes and inhibitors for both exist, this proposal will investigate the possible strategy of inhibition of DNA methylation or histone deacetylation or both as methods to reexpress transcriptionally silent tumor suppressor genes in human breast cancer cells.
The specific aims are: 1. To define the effects of DNA methyltransferase inhibitors, 5-azacytidine or 5-aza 2'-deoxycytidine, on gene expression profiles in human breast cancer cells, 2) to determine the effects of histone dacetylase inhibitors, trichostatin A and phenylbutyrate, on growth and gene expression in human breast cancer cells, 3) to establish whether the combination of a DNA methyltransferase inhibitor and a histone deacetylase inhibitor can lead to enhanced expression of critical growth regulatory genes in human breast cancer cells, and 4) to use custom cDNA arrays to identify gene expression profiles after treatment of human breast cancer cells with a DNA methyltransferase inhibitor or a histone deacetylase inhibitor. It is expected that these studies would lay the foundation for a trial of transcriptionally based therapy in women with advanced breast cancer and contribute to the development of molecular markers for use in other aims.
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