title: Synergistic induction of tumor antigens by Wnt-1 signaling and retinoic acid revealed by gene expression profiling.
abstract: 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.
authors.affiliation: Department of Molecular Oncology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Tice
authors.forename: Wayne
authors.initials: W
authors.lastname: Szeto
authors.forename: Irina
authors.initials: I
authors.lastname: Soloviev
authors.forename: Bonnee
authors.initials: B
authors.lastname: Rubinfeld
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Fong
authors.forename: Debra L
authors.initials: DL
authors.lastname: Dugger
authors.forename: Jane
authors.initials: J
authors.lastname: Winer
authors.forename: P Mickey
authors.initials: PM
authors.lastname: Williams
authors.forename: David
authors.initials: D
authors.lastname: Wieand
authors.forename: Victoria
authors.initials: V
authors.lastname: Smith
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Schwall
authors.forename: Diane
authors.initials: D
authors.lastname: Pennica
authors.forename: Paul
authors.initials: P
authors.lastname: Polakis
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins
chemical_list: D000951:Antigens, Neoplasm; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D029961:Zebrafish Proteins; D014212:Tretinoin; D012313:RNA