We have used the differential display method as a coincidence analysis technique to isolate genes expressed in different rat tissues undergoing physiological apoptosis, such as involuting mammary gland or prostate after castration. One isolate, DDC-4, encodes a secreted Frizzled-Related Protein of 39.7 kD in an open reading frame of 1,044 nucleotides. This protein family is thought to antagonize the signaling of Frizzled transmembrane receptors. Inappropriate expression of DDC-4 in lactating mammary glands of transgenic mice induces apoptosis during late pregnancy and early lactation. DDC-4 presumably acts by blocking a survival pathway. Classical Wnt-Frizzled signaling leads to the stabilization of cytosolic β-catenin and activation of Tcf/Lef transcription factors. Increased activity of this pathway owing to mutations in such genes as tcf-4 or those for adenomatous polyposis coli or β-catenin results in the formation of tumors. In many colorectal carcinomas and tumor models Tcf/Lef-responsive genes are upregulated. Based on the hypothesis that the genes targeted by Tcf/Lef might be at risk for producing tumors when activated by a second, alternative signaling pathway, we analyzed their promoter regions for further, putative, tumor-associated cis-acting elements. The kind of analysis performed is based on the assumption that biologically relevant elements are statistically overrepresented compared with random elements. Since such elements might unravel transcription factor–binding sites active in transformed but not in normal cells, they are candidates for artificial cancer-specific promoters, for which there is an urgent need in several gene-therapy projects.