P53-INDEPENDENT APOPTOSIS DURING MAMMARY-TUMOR PROGRESSION IN C3(1) SV40 LARGE T-ANTIGEN TRANSGENIC MICE - SUPPRESSION OF APOPTOSIS DURING THE TRANSITION FROM PRENEOPLASIA TO CARCINOMA/

Alterations in apoptosis and associated mechanisms during mammary tumo r progression were investigated in transgenic mice expressing the SV40 large T antigen (T-AG) driven by the rat prostatic steroid-binding pr otein C3(1) 5'-flanking region. Apoptosis levels, assessed by in situ end labeling, were low in normal mammary epithelial cells, highest in atypical hyperplasias (preneoplastic lesions), and less pronounced in adenocarcinomas. Preneoplastic cells maintain the ability to undergo a poptosis as a mechanism of tumor growth suppression, but this critical control of apoptosis is lost as these lesions progress to carcinomas. These alterations in apoptosis occur during mammary tumor progression in mice containing wild-type p53(+/+) genotype as well as in mice wit h the p53(-/-) genotype. Thus, apoptosis in this tumor model occurs th rough a p53-independent mechanism. Because other studies have demonstr ated p53-dependent apoptosis in T-AG-induced choroid plexus tumors of transgenic mice, we propose that the role of p53 in apoptosis may be t issue-specific. In addition, bcl-2 protein was not expressed in any ma mmary lesions. SV40 T-AG expression, which correlated with the nuclear p53 protein at all stages of tumor progression, was low in normal mam mary epithelial cells, moderately high in atypical hyperplasias, and s trongly expressed in adenocarcinomas. No p53 mutations were found at a ny stage of mammary adenocarcinoma development, suggesting that tumor progression does not require a dominantly acting p53 mutation in this transgenic model. p21(Waf1/Cip1) a cyclin-dependent kinase inhibitor, was expressed in normal mammary tissue but was not detected in the mam mary carcinomas, despite high nuclear accumulation of wild-type p53 pr otein, suggesting functional loss of p53 due to binding of SV40 T-AG t o p53. These findings suggest that suppression of apoptosis during the transition from atypical hyperplasia to adenocarcinoma appears to be a critical event for mammary cancer development in C3(1)/T-AG transgen ic mice and occurs by p53- and bcl-2-independent pathways.