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 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.
Donehower
L A
LA
Division of Molecular Virology, Baylor College of Medicine, Houston, Texas 77030, USA.
Godley
L A
LA
Aldaz
C M
CM
Pyle
R
R
Shi
Y P
YP
Pinkel
D
D
Gray
J
J
Bradley
A
A
Medina
D
D
Varmus
H E
HE
D000230:Adenocarcinoma / Q000235:genetics* / Q000469:parasitology; D000782:Aneuploidy; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D005355:Fibrosis / Q000473:pathology; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins
D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D029961:Zebrafish Proteins