The etiology of breast cancer. Characteristic alteration in hydroxyl radical-induced DNA base lesions during oncogenesis with potential for evaluating incidence risk.
BACKGROUND
Substantial hydroxyl radical (.OH)-induced base lesions, recently found in the DNA of invasive ductal carcinoma of the female breast, are likely to be intimately related to oncogenesis. However, virtually no information was available regarding relationships between the different base lesions in the normal and cancerous breast. Such information is essential in understanding initial stages in the development of breast cancer and the potential of the base lesions as early predictors of cancer risk.


METHODS
The .OH-induced DNA base lesions in normal reduction mammoplasty tissue (RMT) were compared with those from invasive ductal carcinoma (IDC) and nearby microscopically normal tissue (MNT). Comparisons were then undertaken on relationships between the base lesion profiles in the normal and cancerous breast using 22 statistical models.


RESULTS
DNA from the RMT was characterized by a high ratio of ring-opening products (e.g., 4,6-diamino-5-formamidopyrimidine) to hydroxy-adducts of adenine and guanine. A dramatic shift in this relationship in favor of carcinogenic hydroxy-adducts (e.g., 8-hydroxyguanine) was found in the cancerous breast. Statistical models with a high sensitivity (91%) and specificity (97%) provided a consistent means of classifying tissues (e.g., 96% correct).


CONCLUSIONS
The dramatic shift in the DNA base lesion relationships in oncogenesis is attributed to alterations in the redox potential of the breast favoring oxidative conditions and cancer formation. These findings suggest that base lesion profiles are potential sentinels for cancer risk assessment. Further, intervention in controlling the tissue redox potential may provide benefit in delaying or preventing early oncogenic changes and the ultimate manifestation of cancer.
Malins
D C
DC
Molecular Epidemiology Program, Pacific Northwest Research Foundation, Seattle, Washington 98122.
Holmes
E H
EH
Polissar
N L
NL
Gunselman
S J
SJ
D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000209:etiology* / Q000378:metabolism; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000209:etiology* / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D006801:Humans; D006878:Hydroxides / Q000737:chemistry*; D016462:Mammaplasty; D017382:Reactive Oxygen Species; D012044:Regression Analysis; D012307:Risk Factors
D006878:Hydroxides; D017382:Reactive Oxygen Species