Novel Mouse Model for Genetic Validation of Therapeutic Targets in Breast Cancer

摘要

Our proposal focused on developing a versatile and generic technology platform that allows direct evaluation of the roles played by specific genes (and their products) in the genesis, progression and maintenance of breast cancer. We have constructed genetically modified mice in which c-myc or E2f3 have been modified so as to incorporate a reversible Tet or Lac regulatable switch. This will allow us to switch off (and on) individual target gene and determine what role that gene plays in mammary carcinoma. In effect, we can model the efficacy, specificity and side effects of a drug designed to target that gene's function, either alone or in combination with existing therapies. To date we have generated the targeting constructs for these mice, tested the switchability of the construct in vitro,identified correctly targeted ES cells and generated chimeric mice. Once the targeted mutant mouse lines a reestablished we will combine them with established models of breast carcinogenesis, which will allow us to evaluate their separate and combined roles in driving breast cancer progression, in the maintenance of established tumors,and as therapeutic targets.