PROGRESSION TO ANDROGEN INSENSITIVITY IN A NOVEL IN-VITRO MOUSE MODELFOR PROSTATE-CANCER

We have shown previously that the ras and myc oncogenes can induce poo rly differentiated mouse prostate carcinomas in vivo with high frequen cy (greater than 90%) using inbred C57BL/6 mice in the mouse prostate reconstitution model system. To study the androgen sensitivity of thes e carcinomas, we have developed an in vitro model system which include s a cell line from normal urogenital sinus epithelium (CUGE) and cell lines from three ras+myc transformed mouse prostate carcinomas (RM-9, RM-1, and RM-2). CUGE cells, as well as all prostate carcinoma cell li nes, were positive for cytokeratin 18 mRNA and immunoreactive to cytok eratin-specific antiserum. Two out of three of the early passage carci noma cell lines were clonal with respect to Zipras/myc 9 retrovirus in tegration as determined by Southern blot analysis. Whereas significant mitogenic effects of testosterone (10 nM) were not seen in CUGE cells grown in serum-free medium, under similar conditions approx. 2-fold i ncreases in cell number were seen in all low passage prostate carcinom a cell lines. Also, in the presence of growth inhibitory levels of sur amin (50 mu g/ml), testosterone was capable of significant growth stim ulation in the carcinoma cell lines. With further propagation from low passage [20-25 population doublings (PD)] to high passage (75-100 PD) , all carcinoma cell lines demonstrated increased and similar growth r ate in the presence and absence of testosterone. These cell lines main tained stable androgen receptor numbers and binding kinetics during th e transition from testosterone-responsive growth to reduced responsivi ty over multiple passages in culture (>150 PD). Overall, our studies i ndicate that the capacity to bind testosterone is stably maintained th rough the transition of the androgen-sensitive to insensitive phenotyp e and raise the possibility that androgen sensitivity can persist thro ughout progression but is masked by the acquisition of autocrine pathw ays.