Transgenic models for the study of prostate cancer.

Transgenic model systems provide tools for obtaining information that clarifies important relationships between genetic alterations and carcinogenesis. One such relationship is the induction of specific growth factor activities by dominantly acting oncogenes. Using a "transgenic organ" model referred to as mouse prostate reconstitution (MPR) under conditions where the ras and myc oncogenes were introduced using a recombinant retrovirus into both the mesenchymal and epithelial compartments of the urogenital sinus, poorly differentiated prostate cancer (PC) was produced with high frequency (> 90%) in inbred C57BL/6 mice. Time-course studies using northern blotting and immunohistochemical analysis showed that the transition from benign to malignant status invariably was associated with the induction of elevated transforming growth factor-beta 1 (TGF-beta 1) expression. Additional immunohistochemical analysis of TGF-beta 1 in human PC and benign prostatic hyperplasia (BPH) showed that positive extracellular staining was significantly more extensive in PC compared with BPH. This differential staining pattern was evident in focal areas of PC adjacent to BPH. These findings in both the MPR model system and human PC suggest that elevated TGF-beta 1 expression is involved in the progression to malignancy and that its pattern of expression may become a useful marker of PC. Additional studies using transgenic animal models will continue to provide important clinically useful information about PC in man.