The use of tumor-bearing genetically engineered mouse models may improve preclinical testing of anticancer drugs in guiding clinical trials. These models recapitulate specific molecular pathways in tumor initiation and progression, and provide an in vivo system in which to test efficacy of new therapies. In spite of obvious advantages of testing molecular targeted therapies in GEM, there are significant obstacles in using these models for drug development particularly due to lack of synchronous tumor development. A plausible solution for adapting these valuable tumors for wider use in preclinical testing is transplantation into naïve recipients. Transplanted cell suspensions from MMTV-PyMT, and -wnt1 mammary tumors generated synchronous tumors in naïve syngeneic and immunosuppressed mice. Transplanted tumors had similar morphologic appearance to tumors originating spontaneously in transgenic models, and similar in vivo sensitivity to Paclitaxel or Cyclophosphamide. Gene expression profiles did not distinguish original from serially transplanted tumors, indicating that the genome remained stable in the absence of in vitro manipulation. Analysis of pathways network revealed important features that distinguished the luminal phenotype represented by MMTV-PyMT from the basal phenotype represented by MMTV-wnt1, as well as similarities with human disease. TGF-β1, extensively described in a cross-talk with wnt pathway, MAPK1, TNF and ß-catenin appeared as key nodes connecting many differentially expressed genes specifically in MMTV-wnt1 model. In addition, several proteins that have not been previously directly linked to Wnt1 expression emerged from this analysis and may constitute new therapeutic targets. We propose that transplantation for expansion of GEM tumors in vivo coupled with systematic identification of activated networks by combining gene expression and analysis of activated pathways provide a useful method for developing mouse correlates for human cancer in GEM.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA