Induction of adipocyte-specific gene expression is correlated with mammarytumor regression by the retinoid X receptor-ligand LGD1069 (targretin)

Targretin (LGD1069; a high-affinity ligand for the retinoid X receptors) is an efficacious chemotherapeutic and chemopreventive agent in the N-nitroso -N-methylurea-induced rat mammary carcinoma model. To evaluate the molecula r action of LGD1069 in mammary carcinoma we have examined gene expression p atterns in controls and nonresponding tumors compared with tumors undergoin g regression (responding) by LGD1069, When compared with controls or nonres ponding tumors, the expression of adipocyte-related genes such as adipocyte P2 (aP2), adipsin, peroxisome proliferator-activated receptor gamma (PPAR gamma), and lipoprotein lipase was elevated in LGD1069-responding tumors. F urther analysis showed that gene expression changes occurred rapidly, in as little as 6 h, after the first dose of LGD1069, Immunohistochemical analys is showed that aP2 protein was also highly expressed in responding tumors w hen compared with control or nonresponding tumors. More importantly, aP2 pr otein was localized in the tumor cells in addition to the adipocytes presen t in the tumors. Similar changes in gene expression and inhibition in growt h were seen in tumor cells (cloned from N-nitroso-N-methylurea-induced carc inoma) exposed to LGD1069 in vitro. These data suggest that tumor regressio n by LGD1069 involves differentiation induction along the adipocyte lineage .