Analysis of the TGF β functional pathway in epithelial ovarian carcinoma

Abstract

Summary Epithelial ovarian carcinoma is often diagnosed at an advanced stage of disease and is the leading cause of death from gynaecological neoplasia. The genetic changes that occur during the development of this carcinoma are poorly understood. It has been proposed that IGFIIR, TGFβ1 and TGFβRII act as a functional unit in the TGFβ growth inhibitory pathway, and that somatic loss-of-function mutations in any one of these genes could lead to disruption of the pathway and subsequent loss of cell cycle control. We have examined these 3 genes in 25 epithelial ovarian carcinomas using single-stranded conformational polymorphism analysis and DNA sequence analysis. A total of 3 somatic missense mutations were found in the TGFβRII gene, but none in IGFRII or TGFβ1. An association was found between TGFβRII mutations and histology, with 2 out of 3 clear cell carcinomas having TGFβRII mutations. This data supports other evidence from mutational analysis of the PTEN and β-catenin genes that there are distinct developmental pathways responsible for the progression of different epithelial ovarian cancer histologic subtypes.

Intrahepatic cholangiocarcinoma escapes from growth inhibitory effect of transforming growth factor-β1 by overexpression of cyclin D1

“…43 Somatic mutations of TbR-II are noticeable in hereditary nonpolyposis colorectal cancer, although these mutations are less frequent in most carcinomas without microsatellite instability. 14,15 Taken together, it seems likely that mutation of exon 3, 5, and 7 of TbR-II is a minor mechanism for TGF-b-resistance in ICC cells.…”

“…Somatic mutations of TbR-II were firstly reported in some carcinoma cells, especially hereditary nonpolyposis colorectal cancer, 12,13 though the frequency was found to be relatively low in other carcinomas. 14,15 Other mechanisms of escaping tumor growth inhibition by TGF-b1 such as somatic mutation of Smads, transcriptional downregulation of TGF-b receptors, and overexpression of smad7, are also reported. [16][17][18][19] TGF-b1 is known to inhibit the proliferation of non-neoplastic epithelium at the G1/S phase via several cell cycle-related molecules such as cyclins (cyclins D, cyclin E), cdks (cdk2, cdk4, cdk6), and cdk inhibitors (p15, p21, p27).…”

Expression of TGFß1 and its receptors is associated with biological features of ovarian cancer and sensitivity to paclitaxel/carboplatin

“…Although abnormalities in the expression or function of TGFß1 and its receptors, or molecules in the downstream signaling cascade, have been reported in several studies of ovarian cancer, some authors have reported significant abnormalities, while others have found minor changes and controversy exists (30)(31)(32)(33)(34). In addition, very few studies of ovarian cancer have assessed the associations between TGFß1 expression and the prognosis or sensitivity to anticancer drugs.…”

Dysregulated TGFB Signaling in Ovarian Cancer

“…Specifically, a frameshift mutation has been identified in Exon 5 of TGFRI in 31% of ovarian tumors (Wang et al, 2000b), in exons 2, 3, 4, and 6 of TGFRI (catalytic domain of the kinase) in 33% primary ovarian cancers (Chen et al, 2001), and deletions in exon 1 of TGFRI in <30% of ovarian tumors (Antony et al, 2010). Likewise, missense mutations have been identified in TGFRII (Francis-Thickpenny et al, 2001) and deletions in exon 3 of TGFRII in ovarian tumors (Antony et al, 2010).…”