NEU ERBB2 COOPERATES WITH P53-172H DURING MAMMARY TUMORIGENESIS IN TRANSGENIC MICE/

Thirty percent of human breast cancers have amplification of ERBB2, of ten in conjunction with mutations in p53. The most common p53 mutation in human breast cancers is ab Arg-to-His mutation at codon 175, an al lele that functions in a dominant oncogenic manner in tumorigenesis as says and is thus distinct from loss of p53. Transgenic mice expressing mouse mammary tumor virus-driven nea transgene (MMTV-neu) develop clo nal mammary tumors with a latency of 231 days, suggesting that other e vents are necessary for tumor development. We have examined the role o f mutations in p53 in tumor development in these mice. We have found t hat 37% of tumors arising in these mice have a missense mutations in p 53. We have directly tested for cooperativity between were and mutant p53 in mammary tumorigenesis by creating bitransgenic mice carrying MM TV-neu and 172Arg-to-His p53 mutant (p53-172H). In these bitransgenic mice, tumor latency is shortened to 154 days, indicating strong cooper ativity. None of the nontransgenic mice or the p53-172H transgenic mic e developed tumors within this time period. Tumors arising in the p53- 172H/neu bitransgenic mice were anaplastic and aneuploid and exhibited increased apoptosis, in distinction to tumors arising in p53-null mic e, in which apoptosis is diminished. Further experiments address poten tial mechanisms of cooperativity between the two transgenes. In these bitransgenic mice, we have recapitulated two common genetic lesions th at occur in human breast cancer and have shown that p53 mutation is an important cooperating event in neu-mediated oncogenesis.