Identification of a MMTV Insertion Mutation within the Coding Region of theFgf-3Protooncogene

Abstract

TheFgf-3protooncogene (previously calledint-2) is a target of proviral insertion mutations in mammary tumors induced by the mouse mammary tumor virus (MMTV). These insertion mutations result in the transcriptional activation ofFgf-3,which is not normally expressed in the adult mammary gland. Previous mapping studies of numerousFgf-3insertion mutations have failed to reveal any provirus integrations within the gene coding region. This finding is consistent with the hypothesis that oncogenesis occurs in this system as a consequence of up-regulation ofFgf-3transcription, rather than from alterations of the gene product. During an analysis of a new cohort of tumors from the WXG-2 mouse strain, a breast tumor was identified which had a MMTV provirus integrated 24 bp upstream of theFgf-3stop codon. This insertion mutation generated a fusion transcript which was readily detectable in tumor RNA by RT-PCR. The predicted protein product of this fusion transcript is missing 8 aa of native sequence and contains an additional 8 aa of cryptic MMTV-encoded sequence. These data document the first exception to the generalization that theFgf-3coding region is not disrupted by MMTV insertion mutation.