Insertional Mutation of Int Protooncogenes in the Mammary Tumors of a New Strain of Mice Derived from the Wild in China: Normal- and Tumor-Tissue-Specific Expression of Int-3 Transcripts

Abstract

A new mouse strain, Mus musculus Jyg, has been isolated from the wild In China. After several generations of inbreeding, Jyg mice have been found to develop mammary adenocarcinomas at a high Incidence (70-80%). In order to understand the mechanism by which mammary tumors are induced in these mice, we analyzed 23 available mammary tumors and liver tissues with regard to mouse mammary tumor virus (MMTV) proviral integrations and the pattern of int oncogene (Wnt-1, int-2/Fgf-3, and int-3) rearrangements and expression. We found that (1) Jyg mice do not carry endogenous MMTV; (2) all tumors showed multiple MMTV proviral integrations and expressed high levels of MMTV; (3) Jyg MMTV is distinguishable from other MMTV strains; (4) a high percentage of the tumors (70%) had insertional mutations in int loci (Wnt-1, 26%; int2, 13%; and int 3, 43%); and (5) unlike Wnt-1 and int-2, a 5.9-kb int -3-related transcript is expressed in developing mouse embryos of all stages and adult mouse tissues including mammary tumors, whereas a 2.4- to 3.6-kb transcript is expressed only in Jyg mammary tumors with int -3 mutations. Taken together, this newly developed mouse strain and the milk-borne MMTV that it carries constitute a novel system for studies of the host and viral specificity of insertional mutagenesis of multiple int protooncogenes by MMTV and the role of these genes in the pathogenesis of mouse mammary carcinomas and tumor cell heterogeneity.