Transcriptional repression of fibroblast growth factor 8 by transforming growth factor-β in androgen-dependent SC-3 cells

We here characterized the transcriptional profiles of TGF-β-responsive genes using androgen-dependent mouse mammary carcinoma SC-3 cells. Compared with the testosterone-stimulated SC-3 cells, 165 genes were up-regulated at more than 5-fold, and 78 genes were down-regulated to less than one-third in response to TGF-β. Of note, fgf8, an androgen-inducible growth factor essential to the androgen-dependent growth of SC-3 cells, was severely repressed in response to TGF-β. Real-time PCR confirmed that the androgenic induction of the fgf8 transcripts is severely attenuated by TGF-β. Although a considerable number of growth-suppressive genes were up-regulated in response to TGF-β, the treatment with TGF-β was insufficient to lead SC-3 cells to apoptosis within 24 h by both the TUNEL method and the caspase 3 activity assay. Flow cytometric analysis rather indicated the cell-static effect of TGF-β on the androgen-stimulated SC-3 cells. In addition, TGF-β failed to suppress the FGF8-stimulated growth of SC-3 cells, suggesting that the repression of fgf8 is required for the TGF-β-mediated growth inhibition in SC-3 cells. In a reporter assay, androgen-responsive promoter activity was suppressed by TGF-β in SC-3 cells. Based on this finding, it is likely that some of the androgen-inducible genes are physiological targets of the TGF-β-mediated transcriptional control, and therefore, it is strongly suggested that the repression of fgf8 might be directly or indirectly involved in this transcriptional control by TGF-β.