Discovery of Novel Mammary Developmental and Cancer Genes Using ENU Mutagenesis

摘要

This project sought to discover new genes involved in mammary gland carcinogenesis using ENU mutagenesis. The initial approach involved screening ENU mutagenisized mice for mammary tumors. Screening of 1100 mice by mammary whole mount histology identified a number of pedigrees with mammary tumors attributable to ENU-induced recessive mutation. The authors failed in all cases to recapitulate the original phenotype in subsequent rounds of breeding, indicating the influence of environmental mutagenic events in this initial screen. In their second attempt, they are screening for reduced latency to palpable mammary tumors in response to expression of a doxycycline-inducible myc oncogene that is produced by the loss of a second gene knocked out by random ENU mutagenesis. This screen is currently underway. A number of factors have slowed the progress of this project. First, the unexpected failure of the first screen forced a change in strategy. The new strategy, employing oncogene sensitization, required the import of a mouse model from the United States. Stringent animal house regulations in Sydney and Canberra forced this line to be rederived twice by embryo transplantation. The failure of the first round caused the loss of their space in the ENU facility, and new space only became available following the construction of a new ENU facility in Canberra. Despite these setbacks, the authors are continuing with the project using funds obtained from the Australian NH AND MRC, and hope to discover new oncogenes cooperating with myc during carcinogenesis.