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Aromatic DNA Adducts in Adjacent Tissues of Breast Cancer Patients: Clues to Breast Cancer Etiology¹

Departments of Clinical Investigations [D. L., M. W., W. N. H.] and Breast Medical Oncology [K. D.], University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The etiology of the majority of human breast cancers is unknown. Environmental factors have long been suspected to play a role, but no specific causative agent has been identified. If the hypothesis that environmental carcinogen exposure contributes to human breast cancer is true, carcinogen-DNA adducts would be expected to be present in human breast tissues. To address this possibility, aromatic DNA adducts were measured in 87 surgical specimens of normal human breast tissues from 87 breast cancer patients undergoing mastectomy using the nuclease P1-enhanced version of the ³²P postlabeling assay. Breast tissue samples from 29 noncancer patients undergoing reduction mammoplasty served as controls. Whereas aromatic DNA adducts were detected in all tissue samples examined, the total adduct levels in cancer patients were significantly higher than that in noncancer controls [mean ± SEM, 97.4 ± 23.4/10⁹ nucleotides (range, 3.8–1737.1) versus 18.1 ± 11.6/10⁹ nucleotides (range, 5.6–56.7), respectively; P < 0.01, t test and Mann-Whitney test]. This difference was not affected by the age distribution of the two groups. The typical smoking-related DNA adduct pattern (i.e., a diagonal radioactive zone) was observed in 29 of 87 tissues (17 of 17 current smokers, 5 of 8 former smokers, 4 of 52 nonsmokers, and 3 of 10 patients with unknown smoking status) and in 2 of 10 control tissues. It was of interest that a benzo(a)pyrene (BP)-like DNA adduct was observed in 36 normal adjacent breast tissues (41%), 27 of which were from nonsmokers. Levels of this BP-like adduct were extremely high (> 100/10⁹ nucleotides) in 5 patients (4 nonsmokers and 1 smoker) and moderately high (> 10/10⁹ nucleotides) in 13 other patients (8 nonsmokers and 5 smokers). One patient exhibited this adduct at a level of 1500/10⁹ nucleotides, which is comparable to the highest level of total adducts reported in human tissues related to carcinogen exposure (e.g., cigarette smoking). In contrast, this adduct was absent (<1/10¹⁰ nucleotides) in all of the control tissues. Cochromatography and rechromatography analysis of DNA samples from human breast tissues and from MCF-7 cells treated with BP revealed that this adduct could be generated by BP exposure but is not the major BP 7,8-diol-9,10-epoxide-deoxyguanine adduct detected previously in animal tissues and human mammary epithelial cells. These findings support the hypothesis that environmental carcinogen exposure, in addition to cigarette smoking, may be associated with the etiology of human breast cancer.

¹ This investigation was supported by a grant from University of Texas M. D. Anderson Cancer Center Physicians Referral Service.

² To whom requests for reprints should be addressed, at Department of Clinical Investigation. Box 019. University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 7/27/95. Accepted 11/ 7/95.

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