TY - JOUR
T1 - Expression profiling identifies altered expression of genes that contribute to the inhibition of transforming growth factor-β signaling in ovarian cancer
AU - Sunde, Jan S.
AU - Donninger, Howard
AU - Wu, Kongming
AU - Johnson, Michael E.
AU - Pestell, Richard G.
AU - Rose, G. Scott
AU - Mok, Samuel C.
AU - Brady, John
AU - Bonome, Tomas
AU - Birrer, Michael J.
PY - 2006/9/1
Y1 - 2006/9/1
N2 - Ovarian cancer is resistant to the antiproliferative effects of transforming growth factor-β (TGF-β); 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-β 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-β signaling (DACH1, BMP7, and EVI1) were up-regulated in advanced-stage ovarian cancers and, conversely, genes that enhance TGF-β 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-tune PCR on 11 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-β signaling in immortalized normal ovarian epithelial cells, and a dominant-negative DACH1, DACH1-ΔDS, partially restored signaling in an ovarian cancer cell line resistant to TGF-β. These results suggest that altered expression of these genes is responsible for disrupted TGF-β signaling in ovarian cancer and they may be useful as new and novel therapeutic targets for ovarian cancer.
AB - Ovarian cancer is resistant to the antiproliferative effects of transforming growth factor-β (TGF-β); 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-β 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-β signaling (DACH1, BMP7, and EVI1) were up-regulated in advanced-stage ovarian cancers and, conversely, genes that enhance TGF-β 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-tune PCR on 11 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-β signaling in immortalized normal ovarian epithelial cells, and a dominant-negative DACH1, DACH1-ΔDS, partially restored signaling in an ovarian cancer cell line resistant to TGF-β. These results suggest that altered expression of these genes is responsible for disrupted TGF-β signaling in ovarian cancer and they may be useful as new and novel therapeutic targets for ovarian cancer.
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U2 - 10.1158/0008-5472.CAN-06-0683
DO - 10.1158/0008-5472.CAN-06-0683
M3 - Article
C2 - 16951150
AN - SCOPUS:33749020591
SN - 0008-5472
VL - 66
SP - 8404
EP - 8412
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -