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| Role of estrogen receptor gene demethylation and DNA methyltransferase DNA adduct formation in 5-aza-2 '-deoxycytidine-induced cytotoxicity in human breast cancer cells |
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| Author(s): Ferguson AT, Vertino PM, Spitzner JR, Baylin SB, Muller MT, Davidson NE |
| Source: JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 272 Issue: 51 Pages: 32260-32266 Published: DEC 19 1997 |
| Times Cited: 86 References: 43 |
| Abstract: The cytosine analog 5-aza-2'-deoxycytidine is a potent inhibitor of DNA methyltransferase, Its cytotoxicity has been attributed to several possible mechanisms including reexpression of growth suppressor genes and formation of covalent adducts between DNA methyltransferase and 5-aza-2'-deoxycytidine-substituted DNA which may lead to steric inhibition of DNA function, In this study, we use a panel of human breast cancer cell lines as a model system to examine the relative contribution of two mechanisms, gene reactivation and adduct formation. Estrogen receptor-negative cells, which have a hypermethylated estrogen receptor gene promoter, are more sensitive than estrogen receptor-positive cells and underwent apoptosis in response to 5-aza-2-deoxycytidine. For the first time, we show that reactivation of a gene silenced by methylation, estrogen receptor, plays a major role in this toxicity in one estrogen receptor-negative cell line as treatment of the cells with anti-estrogen-blocked cell death, However, drug sensitivity of other tumor cell lines correlated best with increased levels of DNA methyltransferase activity and formation DNA DNA methyltransferase adducts as analyzed in situ. Therefore, both reexpression of genes like estrogen receptor and formation of covalent enzyme DNA adducts can play a role in 5-aza-2'-deoxycytidine toxicity in cancer cells. |
| Document Type: Article |
| Language: English |
| Reprint Address: Davidson, NE (reprint author), Johns Hopkins Univ, Sch Med, Ctr Oncol, 422 N Bond St, Baltimore, MD 21231 USA |
Addresses:
1. Johns Hopkins Univ, Sch Med, Ctr Oncol, Baltimore, MD 21231 USA
2. Emory Univ, Sch Med, Dept Radiat Oncol, Div Canc Biol, Atlanta, GA 30335 USA
3. Ohio State Univ, Dept Mol Genet, Columbus, OH 43210 USA |
| Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA |
| Subject Category: Biochemistry & Molecular Biology |
| IDS Number: YM852 |
| ISSN: 0021-9258 |
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