LOSS OF P53 FUNCTION LEADS TO METASTASIS IN RAS-INITIATED MOUSE PROSTATE-CANCER(MYC)

To study the interactions between dominantly acting oncogenes and tumo r suppressor genes we used p53 'knockout' mouse urogenital sinus tissu e for retroviral transduction of ras and myc in the mouse prostate rec onstitution (MPR) model system. Epithelial hyperplasia was observed in all wild-type p53 MPRs with one small focal cancer and no evidence of metastasis. Prostatic cancer was found in 100% of the heterozygous an d homozygous p53 mutant MPRs with metastatic deposits in 95% of the mi ce. The pattern of metastasis was remarkably similar to that in human prostate cancer with gross metastatic deposits in the lung, lymph node s, bone and liver of many animals. Progression of carcinomas in the ra s+myc-initiated heterozygous p53 mutant MPRs was invariably associated with either complete loss, partial deletion or loss of expression of the wild-type p53 allele. Southern blotting analysis of proviral-cellu lar DNA junction fragments in primary carcinomas and cell lines derive d from metastatic deposits revealed that metastases do not necessarily seed out from the most abundant clone in the primary carcinoma.