LOSS OF HETEROZYGOSITY ANALYSIS IN PRIMARY MAMMARY-TUMORS AND LUNG METASTASES OF MMTV-MTAG AND MMTV-NEU TRANSGENIC MICE

Loss of heterozygosity (LOH) analysis has been used in many types of h uman cancer to localize putative tumor suppressor genes important in c arcinogenesis, However, this approach has only recently been applied t o transgenic mouse tumor models, which offer greater opportunity for d etailed molecular genetic analysis of tumor initiation and progression , To explore the possible role of secondary genetic events in transgen ic mouse mammary tumor development, we performed microsatellite-based allelo-types on primary mammary adenocarcinomas and lung metastases ar ising in mice transgenic for the polyomavirus middle T antigen under t he control of the mouse mammary tumor virus promoter/enhancer (MMTV-MT Ag mice) and on primary mammary adenocarcinomas arising in mice transg enic for the neu proto-oncogene (MMTV-neu mice). We examined a total o f 80 microsatellite loci distributed throughout the mouse genome for L OB and observed high rates of specific chromosomal loss but very low r ates of background allelic loss in these tumors, For the MMTV-MTAg mic e, no individual chromosomes showed rates of LOH significantly above t he background rates. For MMTV-neu mice, markers on chromosome 4 showed LOH in 82% of mammary tumors, whereas markers on chromosome 3 showed loss in 29% of tumors. These data suggest that the middle T antigen tr ansgenic mice do not undergo whole chromosome loss or large genomic de letions as common mechanisms of tumor formation and that chromosomes 3 and 4 may contain tumor suppressor gene loci that play important role s in the development of neu-mediated mouse mammary tumors.