| Although loss of the TGF-β type II receptor has been correlated with higher prostate tumor grade, it has not been determined whether that loss was a cause or consequence of tumor progression. To determine the effect of an inhibited TGF-β pathway on prostate cancer, we bred transgenic mice expressing the tumorigenic SV40 large T antigen in the prostate with transgenic mice expressing a dominant negative TGF-β type II receptor mutant in the prostate. Transgene(s) and TGF-β1 expression were identified in the prostate and decreased protein levels of plasminogen activator inhibitor type 1, as a marker for TGF-β signaling, correlated with expression of the dominant negative TGF-β type II receptor mutant. Although the sizes of the neoplastic prostates were not greater, increased amounts of metastasis were observed in mice expressing both transgenes compared to age-matched control mice expressing only the large T antigen transgene. Our data, in an animal model of prostate cancer that demonstrates genetic and histopathologic changes analogous to those in human prostate cancer, suggests for the first time that there is a clinically relevant selective advantage for loss of TGF-β regulation as a cause of increased metastasic burden. To determine the molecular differences responsible for the phenotypic change of increased metastasis, microarray analyses of the prostate tumors were performed and showed a total of 996 out of 5000 genes examined with differential fold expression between the two groups of mice. Additionally, statistical analyses demonstrated significant, age-dependent differential gene expression patterns. From the 996 differentially expressed genes, four were selected and confirmed for differential expression by quantitative real time RT-PCR. One of these genes, embigin, was shown to be downregulated by TGF-β treatment in human prostate cancer cell lines and differentially upregulated in human prostate cancer tissue versus benign prostate tissue. Embigin may be a novel target of the TGF-β pathway and a novel determinant of prostate cancer progression. In summary, animal models reflecting a clinical observation were generated, validated, and applied successfully to study the roles of the TGF-β pathway in human prostate cancer. |
