title: Expression profiling identifies altered expression of genes that contribute to the inhibition of transforming growth factor-beta signaling in ovarian cancer.
abstract: 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.
authors.affiliation: Walter Reed Army Medical Center, Washington, District of Columbia, USA.
authors.forename: Jan S
authors.initials: JS
authors.lastname: Sunde
authors.forename: Howard
authors.initials: H
authors.lastname: Donninger
authors.forename: Kongming
authors.initials: K
authors.lastname: Wu
authors.forename: Michael E
authors.initials: ME
authors.lastname: Johnson
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: G Scott
authors.initials: GS
authors.lastname: Rose
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Mok
authors.forename: John
authors.initials: J
authors.lastname: Brady
authors.forename: Tomas
authors.initials: T
authors.lastname: Bonome
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
mesh_terms: D005260:Female; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D006801:Humans; D009367:Neoplasm Staging; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D012334:RNA, Neoplasm; D016212:Transforming Growth Factor beta