© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 3, 214-219,
February 7, 2001
© 2001 Oxford University Press
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Increased Oxidative DNA Damage in Mammary Tumor Cells by Continuous Epidermal Growth Factor Stimulation
Affiliations of authors: J. Hamada, D. Nakata, T. Moriuchi (Division of Cancer-Related Genes), F. Okada, M. Hosokawa (Division of Cancer Pathobiology), Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; D. Nakae, Y. Kobayashi, H. Akai, Y. Konishi, Department of Oncological Pathology, Cancer Center, Nara Medical University, Kashihara, Japan; T. Shibata, Second Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Health Science University of Hokkaido, Tobetsu, Ishikari, Japan.
Correspondence to: Jun-ichi Hamada, Ph.D., Division of Cancer-Related Genes, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060–8638, Japan (e-mail: jhamada{at}med.hokudai.ac.jp).
Background: Growth factors can enhance the malignant potential of tumor cells. To examine the relationship between growth factors and tumor progression, we previously established a weakly malignant cell line, ER-1. We found that a 24-hour exposure of ER-1 cells to epidermal growth factor (EGF) induced malignant properties (tumor progression) that were reversible but that, after a 1-month exposure, these changes were irreversible. In this study, we investigated the irreversible changes induced in ER-1 cells by a 1-month exposure to EGF and the possible involvement of oxidative stress. Methods: ER-1 cells were treated with EGF (100 ng/mL) for 1 month in the presence or absence of an antioxidant, N-acetylcysteine or selenium, and compared with untreated control ER-1 cells. We assessed tumor progression by measuring intracellular peroxide levels, 8-hydroxydeoxyguanosine (a marker for oxidative DNA damage) levels, in vitro invasiveness, and in vivo tumorigenicity and metastatic ability. All statistical tests are two-sided. Results: After ER-1 cells were treated for 1 month with EGF, levels of intracellular peroxide and 8-hydroxyguanosine in the DNA of treated cells were higher than those in the DNA of control cells, and treated ER-1 cells were more tumorigenic and metastatic in vivo and more invasive in vitro than untreated control cells (all P<.001). Levels of 8-hydroxyguanosine in DNA increased as the length of the EGF treatment increased (P<.001). However, when N-acetylcysteine or selenium was added with EGF for 1 month, levels of intracellular peroxide and 8-hydroxyguanosine in DNA were comparable to those in control cells (r = .795). Both tumorigenicity (P = .008) and metastatic ability (P<.001) decreased after addition of N-acetylcysteine or selenium. Conclusion: The irreversible changes caused by continuous EGF stimulation of ER-1 cells result from increased oxidative damage in the DNA, which generates tumor cells with more malignant characteristics.
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