Oncogene and tissue specific pathway activation in an HER2 dependent mouse mammary tumor model

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Breast cancer is the second most prevalent cancer in women with an estimated 216,000 new cases resulting in 40,000 deaths per year. The most prominent oncogenic lesion in breast cancer is amplification of HER2 locus. To better understand and characterize breast cancer with HER2 amplification we generated a complex inducible mouse model based on our chimeric model platform which allows for fast and efficient generation of mouse models. Most prominently the chimeric mouse models provide wildtype tissue for the developing tumor thus mimicking the tumor stroma interactions seen in human tumors. We directed inducible expression of HER2 and Luciferase to the luminal epithelium in the mouse mammary gland by means of the MMTV LTR promoter expressing the rtTA gene. Compromising the p53 and Rb pathway was achieved by inactivating the mouse INK4a/Arf locus by targeted recombination.
 Expression of activated HER2 resulted in invasive adenocarcinomas with a short latency of 2-4 months and a penetrance of 100%. Surprisingly tumors displayed high stroma content reminiscent of human ductal carcinomas.
 We analyzed activation status of major signal transduction pathways like PI3K, MAPK, SAPK and STAT in our primary tumors and were able to establish patterns of pathway activation specific to HER2 dependent tumors as well as patterns specific to mammary gland tumors when compared to lung adenocarcinomas derived from our chimera based HER2 NSCLC model.
 In addition we have characterized the breast HER2 model extensively for progression and regression of inducible tumors as well as variation in histopathological features.
 Furthermore we successfully performed a second site suppression screen for tumor therapy resistance in our breast HER2 tumor cells which most prominently revealed resistance genes implicated in the MET pathway and the ErbB RTK family. The inducibility of our tumor material allowed for direct testing of any tumor therapy resistance genes in in-vivo propagated tumor cells.
 In summary we have expanded the original inducible chimera based Breast Her2 mouse model into a suite of models that provide models/tools for a wide variety of applications in cancer research such as drug testing, analysis of target biology and drug response prediction.