Summary The purpose of the present proposal is to establish genetic models for multistep tumor progression using transgenic mice. The candidate, P. Ruiz, has recently established transgenic mice harbouring a null mutation in the plakoglobin/y- catenin gene; other knockout mice with mutations in the ,B-catenin, E-cadherin, APC and p53 genes have been prepared in the laboratory or are commercially available. Initial crosses between E-cadherin +/- and APC +/- mice have shown that double heterozygous animals develop more and larger tumors, and die earlier than singly heterozygous mice.s mice. In the proposed grant period, the co-operation between the classical tumor suppressor genes, APC and p53, and the
metastasis-suppressing genes of cell adhesion molecules, E-cadherin, a-, B-, and y- catenins, will be elucidated. The individual mutant mouse strains will be interbred, and the tumor pattern of the double mutant mice compared with that of the mutant animals carrying mutations in single genes. From these data we expect essential insights into the genetic cooperation between genes affecting growth and metastasis during tumor progression in vivo.