The long term goal of this proposal is to understand how to control growth of hormone responsive tumors of the male reproductive tract. Two hypotheses are to be tested. the first is that androgens via their receptors stimulate growth by inducing a cascade process which results in the production and/or stabilization of transcripts coding for competence factors; this process can be modified by other regulatory agents such as glucocorticoids, which function via their receptors to decrease the half-life of these androgen induced mRNA's thus maintaining the cells in a G1/G0 or a state. The first hypothesis will be investigated by measuring the concentrations of c-sis, c-fos and c-myc transcriptts as a function of time following testosterone (T) or dihydrotestosterone treatment and investigating the effects of cycloheximide on this process. The time required to establish steady-state levels of sis transcripts will be measure following androgen treatment and then the time required to reach a new steady state following addition of the glucocorticoid triamcinolone acetonide TA) will be determined. After having quantitated the effects of androgens and glucocorticoids on sis, the RNA will be reassayed with a probe for 2'-5'-oligo-A synthetase to determine whether alterations in its expression is associated with changes in concentration of sis transcripts. It will next be determined whether the opposing effects of T and TA on the levels of sis transcripts is explained by changes in half-life of the mRNA and/or alterations regions which are present of the 4.3 kb c-sis transcripts, are involved in glucocorticoid regulatory events by transfection experiments utilizing R3327H-G8-A1 rat prostate cancer cells. In the R3327H-G8-A1 cell line and rat prostate will determine whether reductions in epidermal growth factor (EGF), transforming growth factor alpha (TGF), EGF receptor and c-sis transcripts accompany the glucocorticoid inhibitory effect of growth. Finally, because there appears to be an association with increased expression of c-sis in human BPH and prostate cancer we will test our second hypothesis that abnormal expression of sis is related to abnormal prostatic growth. This will be investigated by producing transgenic mice where the sis gene is placed adjacent to an androgen receptor inducible promoter element.
