Analysis of Multistep Mammary Tumorigenesis in Wnt-1 Transgenic Mice.
Annual rept. 1 Sep 96-31 Aug 97,
CHILDREN'S HOSPITAL LOS ANGELES CA
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Mouse mammary tumor virus MMTV is used as an insertion mutagen in transgenic mice that express the Wnt1 gene in their mammary gland, to produce additional events like activation of a second oncogene. Cloning cellular sequences flanking new proviral insertion from tumor 76 identified a common insertion locus for MMTV. Further analyses of this region identified Fgf3 as the gene activated over a long distance by MMTV. Fgf8 is another oncogene that I identified was activated in 10 of the mammary tumors form these infected Wnt1 transgenic mice. Fgf8 encodes for at least seven different protein isoforms, three of which were isolated by us. These three isoforms Fgf8a, b c differ in their NIH3T3 cell transforming abilities. Fgf8b induces programmed cell death of mammary epithelial cells. This apoptotic property is not confined to Fgf8b but is also seen when mammary epithelial cells are treated with purified human FGF proteins FGF 1, 2, 4, 6, 9. Over expression of BCL2 in the mammary epithelial cells delays the onset of FGF induced apoptosis. Female transgenic mice expressing the Fgf8 gene in the mammary gland developed tumors with a latency of 5-6 months. These tumors were found to be adenocarcinomas benign adenomas to invasive ductal carcinomas. Northern analyses of tumor RNAs show high expression of the transgene.
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