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Oncogenic ß-Catenin Is Required for Bone Morphogenetic Protein 4 Expression in Human Cancer Cells¹

Departments of Oncology [J-S. K., H. C., T. G. N., B. S., T. W.], Pathology [B. S.], and Tumor Biology Training Program [T. G. N.], Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC 20007, and Laboratory of Population Genetics, Center for Cancer Research [T. D., J. J.], National Cancer Institute, Bethesda, Maryland 20892

Somatic cell gene targeting was used to create an isogenic set of human coloncancer cells that differs only in the presence or absence of their endogenous activated ß-catenin oncogene. Affymetrix Genechip expression profiling of parental cells and gene-targeted derivatives identified numerous novel genes whose expression was dependent on the presence of oncogenic ß-catenin. The transforming growth factor-ß family member bone morphogenetic protein 4 (BMP4), whose receptor is mutated in a rare inherited gastrointestinal cancer predisposition syndrome, was the most highly differentially expressed gene. Additional experiments revealed that the oncogenic allele of ß-catenin specifically is absolutely required for BMP4 expression and secretion by human cancer cells and that BMP4 is overexpressed and secreted by human colon cancer cells with mutant adenomatous polyposis coli genes. These data identify the presence of regulatory interactions between the Wnt and BMP signaling pathways in cancer pathogenesis, providing an intriguing connection between the sporadic and inherited forms of a common human malignancy.

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