P53 levels determine outcome during beta-catenin tumor initiation and metastasis in the mammary gland and male germ cells.
beta-Catenin, an oncogene, and P53, a tumor suppressor, are common targets of mutation in human cancers. It has been observed that P53 is often inactivated in tumors involving beta-catenin activation. In an attempt to model this situation in vivo, we crossed the previously characterized MMTV-DeltaN-beta-catenin mouse with the P53 knockout mouse. Female multiparous mice that carry the MMTV-DeltaN-beta-catenin transgene and that are heterozygous for P53 (Tg(DeltaN-betaCat)/+, P53+/-) display an increased tumor burden (2.05 vs 1.31 tumors/animal), with a generally more advanced pathology, and increased metastatic rate (39 vs 0%) relative to transgenic female mice that are wild type for P53 (Tg(DeltaN-betaCat)/+, P53+/+). These differences were not due to complete loss of P53 as only one of 21 tumors demonstrated loss of heterozygosity at the P53 locus. Furthermore, no mutations were present in tumors retaining a single wild-type allele. Tg(DeltaN-betaCat)/+, P53-/- male mice developed testicular teratomas and survived an average of 65 days, whereas non-Tg(DeltaN-betaCat), P53-/- males survived an average of 84 days. Sixty-two percent of Tg(DeltaN-betaCat), P53-/- mice developed testicular teratomas, whereas only 10% of the non-Tg(DeltaN-betaCat), P53-/- mice developed these tumors. These results indicate that the level of P53 and the tissue of origin are important factors in determining outcome of cancer caused by oncogene activation.
Ridgeway
A G
AG
Department of Genetics, Harvard Medical School, Boston, MA, USA.
McMenamin
J
J
Leder
P
P
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019656:Loss of Heterozygosity; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011401:Promoter Regions, Genetic; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013724:Teratoma / Q000235:genetics*; D013736:Testicular Neoplasms / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
C111417:Fam89b protein, mouse; D008565:Membrane Proteins; D011991:Receptors, Virus; D051176:beta Catenin