The observation that advanced prostate cancer has reduced sensitivity to transforming growth factor βI (TGFβI) growth inhibition suggests that the acquisition of TGFβI resistance may play a role in prostate tumor progression. Using the Dunning R3327 rat prostate adenocarcinoma model, it was determined that prostate carcinoma cells became less responsive to TGFβI growth inhibition with differentiated tumors more resistant to TGFβI. A TGFβ receptor defect was not found in advanced prostate carcinoma cells because both the type I and II TGFβ receptors were present and functional. Moreover, TGFα/epidermal growth factor receptor (EGFR) and basic fibroblast growth factor (bFGF)/fibroblast growth factor receptor (FGFR) autocrine stimulatory pathways, which may potentially counter-regulate the inhibitory effects of TGFβI, were not present with prostate cancer progression. However, the likelihood that other prereceptor stimulatory pathways or TGFβ postreceptor signaling alterations are responsible for reduced sensitivity to TGFβI growth inhibition remains to be elucidated.