Novel drug targets can be identified by differential analysis of RNA transcripts isolated from cancer cell lines and tissues. We have extended this approach by analyzing differences in gene expression resulting from the drug treatment of transformed and nontransformed cells. A mouse mammary epithelial cell line (C57MG), which conditionally expresses the Wnt-1 proto-oncogene, was left untreated or treated with retinoic acid in the presence or absence of Wnt-1 expression. The experiment was performed in triplicate, and RNA extracted from the four samples was analyzed by hybridization to over 12,000 unique oligonucleotide probe sets. Reproducible alterations in gene expression that occurred in response to retinoic acid, Wnt-1, or retinoic acid plus Wnt-1 relative to untreated cells were identified. Greater attention was given to genes encoding cell surface antigens that were selectively up-regulated by the combination of Wnt-1 and retinoic acid. These genes included the tumor necrosis factor family 4-1BB ligand, ephrin B1, stra6, autotaxin, and ISLR. Administration of retinoic acid to mice bearing tumors driven by activation of the Wnt-1/beta-catenin pathway resulted in increased expression of stra6 in the tumors but not in normal tissue. In principal, the therapeutic index of antibodies directed against these antigens should be enhanced by co-administration of retinoic acid.