The Loss of TGF-h Signaling Promotes Prostate Cancer Metastasis

In breast and colon cancers, transforming growth factor (TGF)-B signaling initially has an antineoplastic effect, inhibiting tumor growth, but eventually exerts a proneoplastic effect, increasing motility and cancer spread. In prostate cancer, studies using human samples have correlated the loss of the TGF-B type II receptor (TBRII) with higher tumor grade. To determine the effect of an inhibited TGF-B 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 TBRII mutant (DNIIR) in the prostate. Transgene(s) and TGF-B1 expression were identified in the prostate and decreased protein levels of plasminogen activator inhibitor type I, as a marker for TGF-B signaling, correlated with expression of the DNIIR. Although the sizes of the neoplastic prostates were not enlarged, 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 study demonstrates for the first time that a disruption of TGF-B signaling in prostate cancer plays a causal role in promoting tumor metastasis. Neoplasia (2003) 5, 267 – 277