DEFICIENCY OF P53 ACCELERATES MAMMARY TUMORIGENESIS IN WNT-1 TRANSGENIC MICE AND PROMOTES CHROMOSOMAL INSTABILITY

By crossing mice that carry a null allele of p53 with transgenic mice that develop mammary adenocarcinomas under the influence of a Wnt-1 tr ansgene, we have studied the consequences of p53 deficiency in mammary gland neoplasia. In Wnt-1 transgenic mice homozygous for the p53 null allele, tumors appear at an earlier age than in animals heterozygous or wild-type at the p53 locus. About half of the tumors arising in p53 heterozygotes exhibit loss of the normal p53 allele, implying selecti on for p53-deficient cells. Mammary tumors lacking p53 display less fi brotic histopathology and increased genomic instability with aneuploid y, amplifications, and deletions, as detected by karyotype analysis an d comparative genomic hybridization. In one tumor, the amplified regio n of chromosome 7 had an ectopically expressed int-2/FGF3 proto-oncoge ne, a gene known to cooperate with Wnt-1 in the production of mammary tumors. These findings favor a model in which p53 deficiency relaxes n ormal restraints on chromosomal number and organization during tumorig enesis.