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Signaling in Ovarian Cancer β Factor-That Contribute to the Inhibition of Transforming Growth Expression Profiling Identifies Altered Expression of Genes

Ovarian cancer is resistant to the antiproliferative effects of transforming growth factor-B (TGF-B); however, the mechanism of this resistance remains unclear. We used oligonucleotide arrays to profile 37 undissected, 68 microdissected advanced-stage, and 14 microdissected early-stage papillary serous cancers to identify signaling pathways involved in ovarian cancer. A total of seven genes involved in TGF-B signaling were identified that had altered expression >1.5-fold (P < 0.001) in the ovarian cancer specimens compared with normal ovarian surface epithelium. The expression of these genes was coordinately altered: genes that inhibit TGF-B signaling (DACH1, BMP7 , and EVI1) were up-regulated in advanced-stage ovarian cancers and, conversely, genes that enhance TGF-B signaling (PCAF, TFE3, TGFBRII , and SMAD4) were down-regulated compared with the normal samples. The microarray data for DACH1 and EVI1 were validated using quantitative real-time PCR on 22 microdissected ovarian cancer specimens. The EVI1 gene locus was amplified in 43% of the tumors, and there was a significant correlation (P = 0.029) between gene copy number and EVI1 gene expression. No amplification at the DACH1 locus was found in any of the samples. DACH1 and EVI1 inhibited TGF-B signaling in immortalized normal ovarian epithelial cells, and a dominant-negative DACH1, DACH1-#DS, partially restored signaling in an ovarian cancer cell line resistant to TGF-B. These results suggest that altered expression of these genes is responsible for disrupted TGF-B signaling in ovarian cancer and they may be useful as new and novel therapeutic targets for ovarian cancer. (Cancer Res 2006; 66(17): 8404-12)