DEVELOPMENT, PROGRESSION, AND ANDROGEN-DEPENDENCE OF PROSTATE TUMORS IN PROBASIN LARGE T-ANTIGEN TRANSGENIC MICE - A MODEL FOR PROSTATE-CANCER

Probasin (PB) gene product is prostate-specific, epithelial cell in or igin, and androgen-regulated. A large 12-kb promoter fragment of the P B gene (LPB) was linked to the simian virus 40 (SV40) large T antigen (Tag) deletion mutant (that removes the expression of the small t anti gen) to deliver consistently high levels of transgene expression to th e transgenic mouse prostate. Seven male founders, their male offspring , and all the male offspring from two female founders developed at lea st prostatic epithelial cell hyperplasia by 10 weeks of age, indicatin g that the incidence of transformation was 100%. Tumorigenesis in the LPB-Tag animals progressed in a manner similar to that observed in the human prostate. Initially, multifocal proliferating lesions were dete cted in the prostatic epithelium, which continued to progress into hyp erplasia involving the entire epithelium and then low-grade dysplasia. Reactive stromal proliferation was induced and continued to develop t hroughout the progression to high-grade dysplasia, carcinoma in situ, and adenocarcinoma. Immunohistochemical studies indicated that most st romal cells stained positively for both androgen receptor and smooth m uscle alpha-actin, suggesting that stromal overgrowth largely represen ted mesenchymal cells that had differentiated into smooth muscle cells . Epithelial cell transformation was accompanied by the down-regulatio n of differentiated function, as suggested by the loss of dorsolateral prostate-specific secretory proteins. Tumor growth was regarded as an drogen-dependent because tumors regressed in animals castrated at 11 w eeks of age, and androgen treatment restored both epithelial/stromal c ell ratio and tumor growth. Furthermore, small populations of prostati c epithelial cells in castrated animals continued to proliferate, sugg esting the potential for androgen-independent growth. Although prostat ic metastasis to other organs was not observed, local invasion was det ected. In summary, the LPB-Tag animal model is unique in that it is th e only model generated with the Tag alone, thereby eliminating any inf luences of the small t antigen on prostate tumor formation. Moreover, this model undergoes molecular changes similar to those found in human prostate including: (a) the multi-focal nature of tumorigenesis, (b) the progressive histopathologic changes from low-to high-grade dysplas ia similar to human prostatic intraepithelial neoplasia, (c) stimulati on of reactive stromal proliferation, and (d) the androgen-dependent g rowth of the primary tumor. Thus, the LPB-Tag prostate tumor model wil l be useful for studying the sequential mechanisms underlying the deve lopment of multistep tumorigenesis.