ABSTRACT: A rexinoid, targretin (TRG) and two retinoids, 9-cis retinoic acid (9cRA) and 4-hydroxyphenylretinamide (4HPR) were examined for their effects on gene expression in rat mammary gland, liver, and lung tissues. The chemopreventive effects of these agents have largely been attributed to their ability to interact with retinoic acid receptors (RAR) and/or retinoid X-receptors (RXR). TRG interacts with the RXR receptors. 9cRA interacts with both the RAR and RXR receptors, while 4HPR has a moderate affinity primarily for RAR gamma. Based on previously performed mammary chemoprevention studies, TRG (150mg/Kg diet), 9cRA (100 mg/Kg diet), and 4HPR (792 mg/Kg diet), were administrated to rats continually in their diet for 7 days. Tissue - and agent - specific expression differences were determined by comparing tissues from treated rats with those form rats administered a control diet. There were significantly more changes seen associated with TRG than 9cRA or 4HPR. Only a limited number of expression changes were found with 4HPR treatment. For each organ, TRG and 9cRA treated tissues clustered closely together, whereas 4HPR treated tissues clustered with the tissues from the control diet group. In contrast to 9cRA treatment, TRG treatment altered genes that involved fatty acid metabolism and modulation of various cytochromes P450 in the liver clearly demonstrating the very disparate nature of these two retinoids. These expression signatures could provide useful pharmacodynamic biomarkers for retinoidsâ treatment and chemoprevention. Experiment Overall Design: Agent : The 3 agents were obtained from NCI Chemical Repository (Bethesda, MD), Targretin, 9-cis retinoic acid, and 4-hydroxyphenylretinamide. Experiment Overall Design: Rat :Female Sprague-Dawley rats were used (Harlan Sprague-Dawley, Inc. Indianapolis, IN) Experiment Overall Design: Treatment: Starting at 100 days of age, the rats received treatment of TRG (60 mg/kg BW, gavage), 9cRA (100 mg/kg diet), or 4HPR (782 mg/kg diet) for 7 days. At the end of the 7-day treatment, normal mammary gland, liver and lung tissues were collected.
