Mouse mammary tumor virus/v-Ha-ras transgene-induced mammary tumors exhibit strain-specific allelic loss on mouse chromosome 4.
Hybrid mice carrying oncogenic transgenes afford powerful systems for investigating loss of heterozygosity (LOH) in tumors. Here, we apply this approach to a neoplasm of key importance in human medicine: mammary carcinoma. We performed a whole genome search for LOH using the mouse mammary tumor virus/v-Ha-ras mammary carcinoma model in female (FVB/N x Mus musculus castaneus)F1 mice. Mammary tumors developed as expected, as well as a few tumors of a second type (uterine leiomyosarcoma) not previously associated with this transgene. Genotyping of 94 anatomically independent tumors revealed high-frequency LOH ( approximately 38%) for markers on chromosome 4. A marked allelic bias was observed, with M. musculus castaneus alleles almost exclusively being lost. No evidence of genomic imprinting effects was noted. These data point to the presence of a tumor suppressor gene(s) on mouse chromosome 4 involved in mammary carcinogenesis induced by mutant H-ras expression, and for which a significant functional difference may exist between the M. musculus castaneus and FVB/N alleles. Provisional subchromosomal localization of this gene, designated Loh-3, can be made to a distal segment having syntenic correspondence to human chromosome 1p; LOH in this latter region is observed in several human malignancies, including breast cancers. Evidence was also obtained for a possible second locus associated with LOH with less marked allele bias on proximal chromosome 4.
Radany
E H
EH
Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI 48109-0582, USA. Eric_Radany@mailgw.surg.med.umich.edu
Hong
K
K
Kesharvarzi
S
S
Lander
E S
ES
Bishop
J M
JM
D000483:Alleles; D000818:Animals; D002277:Carcinoma / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D011905:Genes, ras; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D012192:Retroviridae Infections / Q000235:genetics*; D013045:Species Specificity; D014412:Tumor Virus Infections / Q000235:genetics*