LOSS OF RESPONSE TO EPIDERMAL GROWTH-FACTOR AND RETINOIC ACID ACCOMPANIES THE TRANSFORMATION OF HUMAN PROSTATIC EPITHELIAL-CELLS TO TUMORIGENICITY WITH V-KI-RAS

Growth factor-independent proliferation and loss of response to differ entiation factors are believed to be critical elements in carcinogenes is, We have developed an Qt vitro model of human prostatic carcinogene sis by the introduction of SV40 DNA into normal prostatic epithelial c ells to create a transformed, immortal cell line, pRNS-1-1. This non-t umorigenic cell line responded similarly to normal prostatic epithelia l cells to most growth- and differentiation-regulatory factors, with t he notable exception of loss of response to the inhibitory factor 1,25 -dihydroxyvitamin D-3, In this study, we describe the introduction of the ras oncogene into pRNS-1-1 cells to create a tumorigenic cell line , pRNS-1-1/ras. In addition to an attenuated response to 1,25-dihydrox yvitamin D-3, these cells also became unresponsive to retinoic acid an d gained the ability to undergo clonal proliferation in the absence of epidermal growth factor (EGF), EGF-independent growth could not be li nked to the production of autocrine transforming growth factor-alpha, but instead was likely due to sustained signaling by the ras oncogene, bypassing ligand-activation of the EGF receptor, Ligand-independent p roliferation, coupled with the loss of response to the growth-inhibito ry and differentiation agent retinoic acid, may be important elements in the conversion of human prostatic epithelial cells to tumorigenicit y.