Abnormal expression of the ATM and TP53 genes in sporadic breast carcinomas

The ataxia telangiectasia gene (ATM) has been implicated as a risk factor i n the development of sporadic breast carcinomas. ATM protein expression was analyzed by immunohistochemistry in 17 breast carcinomas with two monoclon al antibodies whose immunohistochemical use was first validated by comparin g the immunoreactivity observed in spleen samples from ataxia telangiectasi a and trauma patients. In normal breast ducts, ATM showed nuclear expressio n in the epithelial but not in the myoepithelial cells. In contrast, this n uclear expression was absent or low in the epithelial cancer cells in 10 of 17 (59%) of the tumors studied. Allelic imbalance in the ATM gene was foun d in three of seven tumors examined. Two of these showed reduced ATM protei n expression, but this did not correlate with the presence of ATM mutations in the tumor DNA detected by restriction endonuclease fingerprinting scree ning. These results suggest that the reduced ATM protein expression could b e attributable, in certain tumors, to deletions or rearrangements within or close to the ATM gene. Positive p53 immunostaining was found in 10 tumors, with TP53 mutations detected in 8. Three tumors had both low ATM expressio n and mutated TP53. Our results indicate that in the majority (15 of 17) of the sporadic breast carcinomas examined, not only is the functionality of the ATM-p53-mediated DNA damage response compromised, but also other signal ing pathways activated by these two multifunctional proteins are likely to be impaired, which could be a contributing factor to tumor development and progression.