Expression profiling identifies altered expression of genes that contribute to the inhibition of transforming growth factor-β signaling in ovarian cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 17; pp. 8404 - 8412
• Main Authors: SUNDE, Jan S, DONNINGER, Howard, KONGMING WU, JOHNSON, Michael E, PESTELL, Richard G, ROSE, G. Scott, MOK, Samuel C, BRADY, John, BONOME, Tomas, BIRRER, Michael J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-09-2006
• Subjects: Biological and medical sciences; Female; Female genital diseases; Gene Expression Profiling; Genes, Reporter; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Neoplasm Staging; Neoplasms, Cystic, Mucinous, and Serous - genetics; Neoplasms, Cystic, Mucinous, and Serous - pathology; Oligonucleotide Array Sequence Analysis; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Polymerase Chain Reaction; RNA, Neoplasm - genetics; RNA, Neoplasm - isolation & purification; Signal Transduction; Transforming Growth Factor beta - physiology; Tumors; Ovarian diseases; Signal transduction; Transforming growth factor β; Ovary cancer; Inhibitor; Malignant tumor; Gene expression; Female genital diseases; Gene expression profile
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-06-0683

Ovarian cancer is resistant to the antiproliferative effects of transforming growth factor-beta (TGF-beta); 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-beta 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-beta signaling (DACH1, BMP7, and EVI1) were up-regulated in advanced-stage ovarian cancers and, conversely, genes that enhance TGF-beta 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-beta signaling in immortalized normal ovarian epithelial cells, and a dominant-negative DACH1, DACH1-Delta DS, partially restored signaling in an ovarian cancer cell line resistant to TGF-beta. These results suggest that altered expression of these genes is responsible for disrupted TGF-beta signaling in ovarian cancer and they may be useful as new and novel therapeutic targets for ovarian cancer.