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

Authors: Sunde, JS  Donninger, H  Wu, K  Johnson, ME  Pestell, RG  Rose, GS  Mok, SC  Brady, J  Bonome, T  Birrer, MJ 
Citation: Sunde JS, etal., Cancer Res. 2006 Sep 1;66(17):8404-12.
Pubmed: (View Article at PubMed) PMID:16951150
DOI: Full-text: 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.

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CRRD Object Information
CRRD ID: 2299979
Created: 2008-08-22
Species: All species
Last Modified: 2008-08-22
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.