Mouse mammary tumor virus/v-Ha-ras transgene-induced mammary tumors exhibit strain-specific allelic loss on mouse chromosome 4

Abstract

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.

Figure 2

Table (bottom) lists allele lost (C for CAST, F for FVB/N) for six mammary tumors and two sarcomas showing partial LOH on chromosome 4; a + in a cell in the table denotes no allele loss detected. Middle line shows Massachusetts Institute of Technology database marker locations along chromosome 4 (cM, centimorgans), and top section depicts human syntenic correspondence of mouse chromosome 4 subregions (41).

Figure 1

Kinetics of tumorigenesis and occurrence of LOH in female hybrid study mice that had ≥3 litters (A), 1–2 litters (B), or no litters (C). Tumor-free survival is shown as a function of age for each study mouse having a male (•, ○) or female (▪, □) FVB/N transgenic parent. Each symbol at an event timepoint represents one mouse; a filled symbol denotes occurrence of LOH in one or more tumors harvested from that mouse. Tick marks represent mice lost to follow-up without tumor. Tumor-free survival of parous FVB/N transgenic females is shown as the dotted lines in A and B. In C, seven nulliparous study mice developing sarcomas are designated with symbols having triangular inserts that are filled or not to signify LOH; background shading for three of these indicates no genotyping data available. –⋅–⋅, Control nontransgenic F₁ mice.