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

¹ Walter Reed Army Medical Center, Washington, District of Columbia; ² Department of Cell and Cancer Biology and ³ Laboratory of Cellular Oncology Virus Tumor Biology Section, National Cancer Institute, Bethesda, Maryland; ⁴ Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and ⁵ Laboratory of Gynecologic Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Michael J. Birrer, Department of Cell and Cancer Biology, National Cancer Institute, 37 Convent Drive, Room 1130, Bethesda, MD 20892. Phone: 301-402-9586; Fax: 301-480-4756; E-mail: birrerm{at}bprb.nci.nih.gov.

Ovarian cancer is resistant to the antiproliferative effects of transforming growth factor-ß (TGF-ß); 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-ß 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-ß signaling (DACH1, BMP7, and EVI1) were up-regulated in advanced-stage ovarian cancers and, conversely, genes that enhance TGF-ß 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-ß 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-ß. These results suggest that altered expression of these genes is responsible for disrupted TGF-ß 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)

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