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Overexpression of the Retinoic Acid-responsive Gene Stra6 in Human Cancers and Its Synergistic Induction by Wnt-1 and Retinoic Acid

Departments of Molecular Oncology [W. S., W. J., D. A. T., B. R., P. G. H., S. E. F., D. L. D., R. H. S., P. P., D. P.], Pathology [T. P., G. D. F., D. A. E.], Molecular Biology [D. G. Y., J. C. G., J. S. S., C. W. C.], Antibody Technology [T. A. W., B. D.], and Protein Chemistry [R. T. C.], Genentech Inc., South San Francisco, California 94080, and Department of Gene Discovery, CuraGen Corp., New Haven, Connecticut 06511 [L. R.]

Genetic defects in the Wnt-1 signaling pathway contribute to human tumor progression and are especially prevalent in colorectal cancer. We screened mouse C57MG cells to isolate mRNAs induced by Wnt-1 and identified Stra6, an mRNA known to be up-regulated by retinoic acid. Up-regulation of Stra6 mRNA was also observed in hyperplastic mammary tissue and mammary gland tumors from transgenic mice expressing Wnt-1 and in human tumors that frequently harbor defects in Wnt-1 signaling. Stimulation of C57MG cells with retinoic acid plus Wnt-1 resulted in expression of Stra6 transcript to levels greatly exceeding that observed with either stimulus alone. This synergy could be explained in part by the up-regulation of retinoic acid receptor- that was observed in response to Wnt-1 signaling. Accordingly, treatment of human colorectal cancer cell lines with retinoic acid resulted in the up-regulation of Stra6 mRNA and accumulation of Stra6 protein at the cell membrane. The data support a model in which Wnt-1 signaling synergizes with retinoids to activate retinoic acid receptor--responsive genes in human cancers.

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