Increased formation of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, in human breast cancer tissue and its relationship to GSTP1 and COMT genotypes.
Reactive oxygen species (ROS) induced damage to DNA plays a major role in carcinogenesis. In order to estimate the level of oxidative damage and its role in breast cancer, 8-hydroxy-2'-deoxyguanosine (8-OHdG) was determined in DNA isolated from human breast tissue. Furthermore, we investigated whether polymorphisms in genes for enzymes involved in generation and elimination of ROS had any association with the level of 8-OHdG in breast tissue. In this study, the level of 8-OHdG in DNA was measured by the high performance liquid chromatography-electrochemical detector (HPLC-ECD) method. Genotypes of cytochrome P450 (CYP)1A1, glutathione S-transferase (GST)M 1, GSTP1 and catechol O-methyltransferase (COMT) were determined by PCR-based restriction fragment length polymorphism analysis. A total of 61 Japanese patients were included in the study. The mean level of 8-OHdG in DNA of breast cancer tissues was 2.07 +/- 0.95 per 10(5) dG residues, while the mean level of 8-OHdG in DNA of non-cancerous breast tissues was 1.34 +/- 0.46 per 10(5) dG residues. The 8-OHdG levels in DNA of breast cancer tissues were significantly higher than those of their corresponding non-cancerous breast tissues (P < 0.0001). There was negative correlation between the clinical stage and the mean level of 8-OHdG in DNA of breast cancer tissues. Furthermore, patients with genotype of high GSTP1 activity had lower level of 8-OHdG in DNA of breast cancer tissues than others. On the contrary, the mean level of 8-OHdG in DNA of breast cancer tissues was higher among patients with genotype of high COMT activity. Our findings support the assumption that cancer cells are more exposed to oxidative stress than adjacent non-cancerous tissue. Genetic polymorphisms in enzymes involved in ROS metabolism may have a role in individual susceptibility to oxidant-related breast disease. At the same time, reduction of oxidative stress is thought to be a very important measure for primary prevention of breast cancer.
Matsui
A
A
Department of Surgery, Keio University School of Medicine, Tokyo, Japan. matsui@mc.med.keio.ac.jp
Ikeda
T
T
Enomoto
K
K
Hosoda
K
K
Nakashima
H
H
Omae
K
K
Watanabe
M
M
Hibi
T
T
Kitajima
M
M
D000080242:8-Hydroxy-2'-Deoxyguanosine; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D009367:Neoplasm Staging; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen / Q000032:analysis
D007527:Isoenzymes; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D000080242:8-Hydroxy-2'-Deoxyguanosine; D019363:Cytochrome P-450 CYP1A1; D002394:Catechol O-Methyltransferase; D005982:Glutathione Transferase; D003849:Deoxyguanosine