Expression Profiling Identifies Altered Expression of Genes That Contribute to the Inhibition of Transforming Growth Factor-β Signaling in Ovarian Cancer
-
- Jan S. Sunde
- 1Walter Reed Army Medical Center, Washington, District of Columbia;
-
- Howard Donninger
- 2Department of Cell and Cancer Biology and
-
- Kongming Wu
- 4Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and
-
- Michael E. Johnson
- 5Laboratory of Gynecologic Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
-
- Richard G. Pestell
- 4Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and
-
- G. Scott Rose
- 1Walter Reed Army Medical Center, Washington, District of Columbia;
-
- Samuel C. Mok
- 5Laboratory of Gynecologic Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
-
- John Brady
- 3Laboratory of Cellular Oncology Virus Tumor Biology Section, National Cancer Institute, Bethesda, Maryland;
-
- Tomas Bonome
- 2Department of Cell and Cancer Biology and
-
- Michael J. Birrer
- 2Department of Cell and Cancer Biology and
抄録
<jats:title>Abstract</jats:title> <jats:p>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-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-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. (Cancer Res 2006; 66(17): 8404-12)</jats:p>
収録刊行物
-
- Cancer Research
-
Cancer Research 66 (17), 8404-8412, 2006-09-01
American Association for Cancer Research (AACR)
- Tweet
キーワード
詳細情報 詳細情報について
-
- CRID
- 1360574093978709760
-
- ISSN
- 15387445
- 00085472
-
- データソース種別
-
- Crossref