THE INDUCTION OF UTERINE LEIOMYOMAS AND MAMMARY-TUMORS IN TRANSGENIC MICE EXPRESSING POLYOMAVIRUS (PYV) LARGE-T (LT) ANTIGEN IS ASSOCIATED WITH THE ABILITY OF PYV LT ANTIGEN TO FORM-SPECIFIC COMPLEXES WITH RETINOBLASTOMA AND CUTL1 FAMILY MEMBERS

The inactivation of certain tumor suppressor genes is thought to play an important role in the genesis of a number of tumor types. For examp le, inactivation of the Retinoblastoma (Rb) tumor suppressor is freque ntly observed in a proportion of sporadic human breast cancers. While these studies suggest that inactivation of key tumor suppressor genes may play an important role in the induction of mammary cancers, direct evidence supporting this contention is lacking. Because polyomavirus (PyV) Large T (LT) antigen is known to associate with and inactivate c ertain members of the Rb family (p105Rb, p107, p130), we have derived transgenic mice which express PyV LT antigen in the mammary epithelium , As expected mammary epithelial-specific expression of PyV LT antigen resulted in the induction of mammary tumors which correlated with the ir capacity to associate with Rb family members. In addition to mammar y carcinomas, female transgenic mice expressing the PyV LT transgene f requently develop uterine leiomyomas, Because loss of heterozygosity i nvolving the human CUTL1 (Cut like 1) gene located at chromosomal posi tion 7q22 has been recently implicated in sporadic human uterine leiom yomas, we tested the hypothesis that PyV LT antigen may also form spec ific complexes with CUTL1, The results of these analyses revealed that specific complexes of CUTL1 and PyV LT antigen could be detected in b oth leiomyomas and mammary tumors. Taken together, these observations suggest that PyV LT antigen may be involved in inducing these tumors b y sequestering both CUTL1 and Rb growth regulatory proteins.