A NOVEL NON-MOUSE MAMMARY-TUMOR VIRUS-ACTIVATION OF THE INT-3 GENE INA SPONTANEOUS MOUSE MAMMARY-TUMOR

In a mouse mammary tumor model system in which carcinogenic progressio n can be investigated, we have found a unique mutation of Int-3 associ ated with progression from premalignant lobular hyperplasia to tumor. Sequence analysis of the rearranged fragment revealed an insertion of an intracisternal type A particle (IAP) within the Int-3 gene. Int-3 i s mutated frequently in mouse mammary tumor virus (MMTV)-induced mamma ry tumors by insertion of MMTV proviral DNA into this intragenic regio n. In these mutations, the insertion produces a chimeric Int-3 transcr ipt encoding the cytoplasmic portion of the Int-3 protein driven by th e MMTV long terminal repeat promoter. In this case, the IAP DNA was in serted in the opposite transcriptional orientation relative to Int-3; nevertheless, a similar chimeric RNA transcript driven by a cryptic pr omoter in the oppositely oriented 5' IAP long terminal repeat was gene rated. This is the first demonstration that an insertional mutation un related to MMTV activates an Int gene commonly associated with mammary tumorigenesis.