RETINYL METHYL-ETHER DOWN-REGULATES ACTIVATOR PROTEIN-1 TRANSCRIPTIONAL ACTIVATION IN BREAST-CANCER CELLS

Retinyl methyl ether (RME) is known to prevent the development of mamm ary cancer, However, the mechanism by which RME exerts its anticancer effect is presently unclear, The diverse biological functions of retin oids, the vitamin A derivatives, are mainly mediated by their nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RX Rs). RARs and RXRs are ligand-dependent transcriptional factors that e ither activate gene transcription through their binding to retinoic ac id response elements or repress transactivation of genes containing th e activator protein 1 (AP-1) binding site, Previous studies demonstrat ed that RME can modulate transcriptional activity of retinoid receptor s on retinoic acid response elements, suggesting that regulation of re tinoid receptor activity may mediate the anticancer effect of RME. In this study, we present evidence that RME can down-regulate AP-1 activi ty induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, insulin, growth factors, and the nuclear proto-oncogenes c-Jun and c- Fos, Transient transfection assays demonstrate that inhibition of AP-1 activity occurs on the human collagenase promoter containing an AP-1 binding site or the thymidine kinase promoter linked with an AP-1 bind ing site, In HeLa cells, the inhibition is observed when RAR-alpha and /or RXR-alpha but not RAR-beta or RAR-gamma expression vectors are cot ransfected, whereas the endogenous retinoid receptors in breast cancer cells T-47D and ZR-75-1 were sufficient to confer the inhibition by R ME. Furthermore, using gel retardation assay, we show that 12-O-tetrad ecanoylphorbol-13-acetate- and epidermal growth factor-induced AP-1 bi nding activity in breast cancer cells is inhibited by RME. These resul ts suggest that one of the mechanisms by which RME prevents cancer dev elopment may be due to the repression of AP-1-responsive genes.