Early alterations in ras protooncogene mRNA expression in testosterone and estradiol-17 beta induced prostatic dysplasia of noble rats.

The simultaneous treatment of intact Noble rats with testosterone and estradiol-17 beta for 16 weeks consistently induces intraductal dysplasia exclusively in the dorsolateral lobe (DLP) of the prostate. The lesion closely resembles human prostatic dysplasia and is considered to be a preneoplastic alteration, since invasive carcinoma frequently develop after long-term treatment of rats with both steroids. In our current study, we investigated steady-state ras transcript expression at the earliest recognized stages of sex steroid-induced dysplasia in the DLP. Our interest in studying ras expression in these evolving lesions stems from the pivotal role this family of genes are thought to play in the regulation of cell division and differentiation as well as in the genesis of a variety of human and animal neoplasms. Northern blotting and in situ hybridization were used to study ras protooncogene mRNA expression in the DLPs of NBL rats harboring sex steroid-induced ductal dysplasia and to compare findings with those from prostates of castrated and castrated androgen-treated animals. Since the prostate is an androgen-dependent gland, alterations in ras expression were compared with changes in the transcript levels of two androgen-responsive genes that encode for a prostatic secretory protein, seminal vesicle secretion protein II, and the androgen receptor. Similar to the situation for androgen receptor expression, orchiectomy initially enhanced levels of both H- and K-ras transcripts, whereas T administration to castrates was found to return the values to levels found in intact rats. Sixteen weeks of T and E2 administration to intact rats caused levels of H-ras mRNA and a 2.4 kb K-ras transcript to rise by 50 and 60%, respectively in the DLPs with dysplasia when compared with counterpart lobes from untreated control animals. In situ hybridization revealed markedly enhanced H-ras expression in some dysplastic DLP foci and no changes in histologically normal ducts and acini. Taken together, results from our studies suggest that the enhanced focal expression of ras protooncogenes may participate in early aberrant proliferation of prostatic ductal cells of the DLP. Early alterations of ras expression in dysplastic lesions may therefore be a key contributing event in the multistage development of prostate cancer in this animal model.