MOUSE CANCER MODELS VIA TGF-BETA RII LOSS

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Cancers of the prostate, colon and breast comprise a majority of human solid tumors. Disruption of TGFbeta signaling, notably through attenuation or functional loss of the type II TGFbeta receptor (TbetaRII), has been identified in these three human cancers. Preliminary data demonstrate malignant histological changes in prostatic and colonic epithelium of transgenic mice with a widely-expressed metallothionein promoter/enhancer dominant negative TGFbetaRII (DNIIR) cDNA and malignant histological changes in the mammary gland of mice expressing a more restricted MMTV-DNIIR cDNA. We now propose to develop mouse models of these three common cancers by organ selective reduction or elimination of TbetaRII. Histological characterization of these models will be conducted by pathologists expert in mouse and human prostate, colorectal and mammary neoplasia. Validation to their human counterparts will be enabled by comparative histopathological analysis, cDNA microarray expression and mass spectrometric fingerprinting In addition to disrupted TGFbeta signaling, convincing epidemiological and experimental data support a role for cyclooxygenase-2 (COX-2) in the pathogenesis of human colorectal cancer and studies suggest a link between COY-2 and human prostate and breast cancer. Expression of COX-2 and its metabolites will be examined in these three models. It is anticipated that COX-2 expression and responsiveness to NSAIDS will be additional validators of these models. Chemoprevention with selective COX-2 inhibitors, as well as innovative treatment strategies, will be performed. These approaches will be underwritten, in part, by the Vanderbilt Cancer Center and will take advantage of Vanderbilt's experience in development and utilization of mouse models, strengths in growth factor research, and unique expertise and analytical capabilities in eicosanoid biology. In future directions, we propose a "consortium within a consortium" plan to develop a mouse model of ductular pancreatic carcinoma, as well as a strategy to identify modifier genes to nutritional aspects of colorectal cancer.