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Oncology Center [J-P. J. I., S. B. B.] and Department of Medicine [S. B. B.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, and Inhalation Toxicology Research Institute [S. A. B.], Albuquerque, New Mexico 87185
Promoter methylation has recently been shown to be an alternative to mutation in inactivating tumor suppressor genes in human neoplasia. Although specific carcinogen exposures have been associated with characteristic mutation patterns in genes, the factors that lead to promoter hypermethylation remain unknown. One gene target for inactivation through promoter methylation is the estrogen receptor (ER). The purpose of this investigation was to determine the methylation status of this gene in lung tumors from smokers and those who never smoked and in rodents exposed to specific environmental carcinogens. Promoter methylation at the ER locus was detected in 4 of 11 tumors from never-smokers (36.4%) and 7 of 35 tumors from smokers (20%, P < 0.001). Lung tumors induced by the tobacco-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone also had a low incidence (16.7%) of ER methylation. In marked contrast, spontaneous and plutonium-induced tumors had a very high (81.8%) incidence of ER methylation. X-ray-induced tumors had an intermediate frequency of ER methylation (38.1%). The presence of ER methylation was associated with absent ER expression in rodent lung cancer cell lines. These results show for the first time that gene-specific promoter methylation can be modulated differentially depending on carcinogen exposure.
1 This work was supported by a Young Investigator Award from The American Society of Clinical Oncology (to J-P. J. I.), ACS Grant IRG1134, NIH Grant 5P50CA58184, and by the Office of Health and Environmental Research, U.S. Department of Energy under Contract DE-AC04-76-EV01013 in facilities fully accredited by the American Association of Laboratory Animal Care.
2 To whom requests for reprints should be addressed, at Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, MD 21231.
Received 5/22/96. Accepted 7/ 1/96.
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