MMTV-FGF8 TRANSGENIC MICE DEVELOP MAMMARY AND SALIVARY-GLAND NEOPLASIA AND OVARIAN STROMAL HYPERPLASIA

Prior studies have identified Fibroblast Growth Factor-8 (Fgf8) as a p ossible proto-oncogene in mouse mammary tumorigenesis. We now report o n the generation of two types of Fgf8 transgenic mice that each utiliz e the mouse mammary tumor virus (MMTV) promoter. The first transgene ( MMTV-Fgf8b) results in the overexpression of the FGF8b isoform exclusi vely. Male and female MMTV-Fgf8b transgenic mice are viable and fertil e. RNA for FGF8b is detected in mammary gland and salivary gland tissu es of transgenic mice by Northern blot analysis. Nearly 85% of breedin g transgenic female mice developed mammary lobular adenocarcinomas by 12 months of age, while no tumors developed in nontransgenic littermat es. Salivary gland tumors occurred in some animals, always in associat ion with mammary tumors. Several MMTV-Fgf8b transgenic mice had lung m etastases at necropsy. The second transgene (MMTV-Fgf8) uses the entir e Fgf8 gene and potentially encodes all FGF8 isoforms. Fgf8 is express ed by this transgene in several tissues in addition to those described above, notably the ovaries. The two MMTV-Fgf8 founders developed mamm ary ductal adenocarcinomas at five and eight months of age, and both d isplayed ovarian stromal hyperplasia. The founders expressing either t ransgene did not successfully nurse their pups. These results demonstr ate that production of FGF8b, and possibly other FGF8 isoforms, in the mammary and salivary glands contributes to oncogenesis, and that ovar ian expression results in stromal hyperplasia.