The Core will perform two major functions: We will assist with the generation and analysis of xenograft tumor models, and generate novel genetically engineered mouse models for prostate tumorigenesis. The generation and analysis of xenografts tumor models is time consuming and requires specific technical expertise. We will provide technical assistance and training to facilitate the use of xenograft models. A major bottle-neck in the testing and generation of better mouse models of prostate cancer is combining standard genetic models with specific additional mutations. We will generate experimental animals in the Core, thereby removing much ofthe initial burden of complex transgenic experiments from the individual Projects within this Program. This will facilitate the use of such genetic models, and will minimize cost and delays due to lack of access to genetic models and lack of resources. Specifically, in support of the Aims of the three Projects within the Program we will: 1) Provide technical support and training for in vivo xenograft experiments and tumor imaging. Members ofthe Core will be involved in the planning and initiation of xenograft experiments, and will assist with in vivo imaging, induding Xenogen imaging and X-ray imaging of metastases to bone. 2) Generate novel combinations of genetic alterations in mice to address roles in prostate tumorigenesis. We will combine novel conditional mutations in Rala and Ralb with prostate specific deletion of the Pten tumor suppressor. Additionally, we will analyze a series of prostate specific PKN1 transgenes, and combine the most informative with a transgene in which constitutively active AKT1 is expressed in the prostate. 3) Generate mice with a targeted Pkn1 conditional null allele. Mice will be generated from ES cells with a targeted conditional mutation in the Pkn1 gene, and prostate-specific deletion of Pkn1 will be combined with the Pten null mutation, 4) Transfer transgenic prostate tumor models to a pure FVB strain background. All mutations will be transferred to a pure FVB strain background to simplify the analysis of prostate specific tumor phenotypes. By providing these services, we will allow the Program to begin to analyze prostate cancer progression more effectively using animal models.
Prostate cancer is the second leading cause of deaths due to cancer in men in the US. The PTEN gene is a frequently mutated tumor suppressor, and deletions or mutation in PTEN are observed in 30% of primary human prostate cancers, as well as more than 60% of prostate metastases. We will generate novel transgenic prostate cancer models that test the role of the PTEN signaling pathway in prostate cancer progression, and analyze prostate tumor progression in vivo.
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