CORRELATION OF THE ABILITY OF RETINOIDS TO INHIBIT PROMOTER-INDUCED ANCHORAGE-INDEPENDENT GROWTH OF JB6 MOUSE EPIDERMAL-CELLS WITH THEIR ACTIVATION OF RETINOIC ACID RECEPTOR-GAMMA

Retinoids inhibit the biological effects induced in mouse epidermal ce lls by the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Specific nuclear retinoic acid receptors (RARs) have been identified in the epidermis, but the specific receptor that mediates the inhibito ry response by retinoids is not established. Retinoic acid and six con formationally restricted retinoids were evaluated in an in vitro bioas say using the JB6 mouse epidermal cell line. These activities were the n compared with the ability of these retinoids to activate the RARs in transient transfection assays for transcriptional activation to ident ify the retinoid receptor involved in inhibiting TPA-induced anchorage -independent growth. The retinoids inhibited TPA-induced colony format ion of JB6 cells in semisolid medium at concentrations that were not t oxic based on colony formation of attached cells. These concentrations ranged from less than 10(-9)-10(-6) M. trahydro-5,5,8,8-tetramethylan thracen-2-yl)benzoic acid (TTAB) was the most potent retinoid, with an EC50 of 0.8 nM. Both RARalpha and RARgamma were expressed in JB6 cell s. Expression of RARbeta was not detected in these cells using a polym erase chain reaction assay, consistent with its extremely low level in mouse skin. Inhibition of the TPA response by these retinoids in JB6 cells correlated only with their transcriptional activation of RARgamm a, but not with that of RARalpha. These results suggest that RARgamma is most probably the receptor that mediates the chemopreventive effect s of retinoids in mouse epidermis.