Deficiency of p53 accelerates mammary tumorigenesis in Wnt-1 transgenic mice and promotes chromosomal instability

Lawrence A. Donehower, Lucy A. Godley, C. Marcelo Aldaz, Ruth Pyle, Yu Ping Shi, Dan Pinkel, Joe Gray, Allan Bradley, Daniel Medina, Harold E. Varmus

Research output: Contribution to journalArticle

244 Scopus citations

Abstract

By crossing mice that carry a null allele of p53 with transgenic mice that develop mammary adenocarcinomas under the influence of a Wnt-1 transgene, 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 selection for p53-deficient cells. Mammary tumors lacking p53 display less fibrotic histopathology and increased genomic instability with aneuploidy, amplifications, and deletions, as detected by karyotype analysis and comparative genomic hybridization. In one tumor, the amplified region of chromosome 7 had an ectopically expressed int-2/FGF3 proto-oncogene, a gene known to cooperate with Wnt-1 in the production of mammary tumors. These findings favor a model in which p53 deficiency relaxes normal restraints on chromosomal number and organization during tumorigenesis.

Original languageEnglish (US)
Pages (from-to)882-895
Number of pages14
JournalGenes and Development
Volume9
Issue number7
DOIs
StatePublished - Apr 1 1995

Keywords

  • Wnt-1
  • genomic instability
  • mammary tumors
  • mouse
  • p53
  • tumor model

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Donehower, L. A., Godley, L. A., Aldaz, C. M., Pyle, R., Shi, Y. P., Pinkel, D., Gray, J., Bradley, A., Medina, D., & Varmus, H. E. (1995). Deficiency of p53 accelerates mammary tumorigenesis in Wnt-1 transgenic mice and promotes chromosomal instability. Genes and Development, 9(7), 882-895. https://doi.org/10.1101/gad.9.7.882