FGF-8, ACTIVATED BY PROVIRAL INSERTION, COOPERATES WITH THE WNT-1 TRANSGENE IN MURINE MAMMARY TUMORIGENESIS

We have used mouse mammary tumor virus (MMTV) infection of Wnt-1 trans genic mice to accelerate mammary tumorigenesis and to molecularly tag insertionally activated proto-oncogenes that Cooperate oncogenically w ith Wnt-1 (G. M. Shackleford, C. A. MacArthur, H. C. Kwan, and H. E. V armus, Proc. Natl. Acad. Sci, USA 90:740-744, 1993). Here we report th e identification and characterization of a 31-kb genomic locus that co ntains clonal MMTV integrations in 8 of 80 mammary tumors from MMTV-in fected Wnt-1 transgenic mice. Two genes were identified within this lo cus, one of which was transcriptionally activated by MMTV insertions. This activated gene is identical to androgen-induced growth factor (AI GF/Fgf-8) (A. Tanaka, K. Miyamoto, N. Minamino, M. Takeda, B. Sato, H. Matsuo, and K. Matsumoto, Proc. Natl. Acad. Sci. USA 89:8928-8932, 19 92), the eighth member of the fibroblast growth factor (FGF) family. T ranscriptional activation of Fgf-8 was found in all tumors with MMTV i nsertions in this locus. Fgf-8 mRNA was absent in normal mammary gland s and was detected only in adult testis and ovary and in midgestationa l embryos. The sequences of Fgf-8 genomic and cDNA clones revealed fiv e coding exons, in contrast to the three coding exons found in other F GF genes, cDNAs encoding three isoforms of the FGF-8 protein were isol ated. The three corresponding mRNAs resulted from the alternative use of two 5' splice sites and two 3' splice sites for the second and thir d exons, respectively. These results implicate Fgf-8 as the third FGF gene found to cooperate with Wnt-1 in MMTV-induced murine mammary tumo rigenesis, suggesting that FGFs and Wnts are strong collaborators in t his process.