?-Catenin mutation and expression analysis in ovarian cancer: Exon 3 mutations and nuclear translocation in 16% of endometrioid tumours

Wright, Kim; Wilson, Peter J.; Morland, Sarah J.; Campbell, Ian; Walsh, Michael D.; Hurst, Terry; Ward, Bruce G.; Cummings, Margaret C.; Chenevix-Trench, Georgia

doi:10.1002/(sici)1097-0215(19990827)82:5<625::aid-ijc1>3.0.co;2-2

Cited by 123 publications

(80 citation statements)

References 16 publications

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“…Integrin clustering alters E-cadherin and ␤-catenin dynamics, inducing nuclear translocation of ␤-catenin and transcriptional activation of Wnt/␤-catenin target genes. Although some of these genes may also be activated by other pathways, the current data support the hypothesis that matrix-induced integrin clustering may expand the pool of transcriptionally active ␤-catenin and provide a novel mechanism for the dysregulation of Wnt signaling observed in ovarian tumors lacking mutations in the Wnt signaling pathway (23)(24)(25)(26). .…”

Section: Discussionsupporting

confidence: 69%

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Burkhalter

Symowicz

Hudson

et al. 2011

Journal of Biological Chemistry

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Reversible modulation of integrin-regulated cell-matrix adhesion and epithelial (E)-cadherin-mediated cell-cell adhesion plays a critical role in the establishment of ovarian cancer metastases. In contrast to most epithelial cell-derived tumors that down-regulate E-cadherin expression during progression, acquisition of E-cadherin expression accompanies malignant transformation of the ovarian surface epithelium and is maintained in peritoneal metastases. Metastatic epithelial ovarian cancer cells are disseminated intraperitoneally and preferentially adhere via integrins to interstitial collagens in the peritoneal cavity. This study was undertaken to determine whether integrin engagement influences E-cadherin and ␤-catenin localization and function. The data demonstrate that multivalent integrin engagement results in increased internalization of E-cadherin, inhibition of GSK-3␤, elevated levels of nuclear ␤-catenin, increased ␤-catenin-regulated promoter activation, and transcriptional activation of Wnt/␤-catenin target genes. Blocking ␤-catenin transcriptional control with inhibitor of ␤-catenin and Tcf-4 reduces cellular invasion, suggesting a key role for ␤-catenin nuclear signaling in EOC invasion and metastasis. These studies support a model wherein cell-matrix engagement regulates the functional integrity of cell-cell contacts, leading to increased ␤-catenin nuclear signaling and enhanced cellular invasive activity. Furthermore, these results provide a mechanism for activation of Wnt/␤-catenin signaling in the absence of activating mutations in this pathway.Epithelial (E) 3 -cadherin is a single-span transmembrane glycoprotein that mediates calcium-dependent cell-cell adhesion via interaction with the extracellular domains of cadherins on the surface of neighboring cells (1, 2). Key functions of E-cadherin include the regulation of cell polarity and the maintenance of epithelial organization (3). Although most normal epithelia express high levels of E-cadherin, this cadherin is absent in the mesenchymally derived normal ovarian surface epithelium, which expresses neural (N)-cadherin. In most carcinomas, E-cadherin expression is down-regulated or lost, facilitating cellular dispersal, invasion, and metastasis (4). However, a unique feature of EOC is that E-cadherin becomes more abundant in primary differentiated carcinomas, with all histotypes displaying strong immunoreactivity (reviewed in Refs. 5, 6). There is less clarity regarding relative E-cadherin levels during ovarian tumor progression and metastasis. Although complete loss of E-cadherin is uncommon, reduced staining is often detected in late stage tumors and in ascites-derived tumor cells (7-9), and negative E-cadherin is predictive of poor overall survival (10, 11).␤-Catenin is found predominantly in association with the E-cadherin cytoplasmic domain at cell-cell junctions (12). In the absence of cell-cell contact and Wnt signaling, cytosolic ␤-catenin forms a complex with adenomatous poliosis coli, Axin/conductin, casein kinases 1␣ and 1⑀, and glyc...

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Section: Discussionsupporting

confidence: 69%

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Burkhalter

Symowicz

Hudson

et al. 2011

Journal of Biological Chemistry

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“…In our study, the bcatenin gene from SPT contains a somatic mutation, which changes from serine to cysteine. This S33C mutation has been identified in b-catenin genes of various tumors 15,[18][19][20] and this serine has been shown to be mutated in other SPTs. 10 On the basis of these findings, it is suggested that the Wnt signaling is associated with b-catenin mutations and may play an important role in tumorigenesis of SPT.…”

Section: Discussionmentioning

confidence: 99%

Loss of cell-adhesion molecule complexes in solid pseudopapillary tumor of pancreas

et al. 2007

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Solid pseudopapillary tumor of pancreas (SPT) is a rare neoplasm that occurs most often in young females with the two distinct features, the 'solid-cystic' gross appearance, and the 'solid-pseudopapillary' microscopic pattern. It has been reported that almost all SPT tumors contain a mutation in the b-catenin gene; however, the histogenetic origin of this tumor remains largely a mystery. E-cadherin is a cell adhesion molecule that links to catenins to form cell adhesion junctions, which is associated with the cytoskeleton formation. In this study, we examined the expression of E-cadherin and b-catenin from SPT in an attempt to determine the molecular basis for the unusual morphology of this tumor. Nine cases of SPT were retrieved from Surgical Pathologic Archives of three institutions, including one male and eight females. H&E slides of each case were reviewed to confirm the diagnosis. The b-catenin gene was sequenced in one case. E-cadherin and b-catenin immunostains, were performed on all nine cases. Sequencing analysis on one case showed a point mutation of the b-catenin gene, confirming previous findings that almost all SPT tumors contain mutation in the b-catenin gene. Immunostains showed that, in both solid and pseudopapillary areas, all the tumor cells lost expression of E-cadherin, and bcatenin nuclear expression was observed in all cases. Our findings suggest that loss of cytoplasmic b-catenin protein in the cell adhesion complex due to b-catenin gene mutation, results in instability of the complex, loss of E-cadherin in cell membrane, and eventually dissociation of the tumor cells to form the pseudopapillary pattern. Modern Pathology (2007) 20, 509-513.

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“…The possibility of distinct developmental pathways for epithelial ovarian cancer subtypes has been suggested previously. Somatic mutations in the PTEN (Obata et al, 1998) and β-catenin (Wright et al, 1999) genes are found most frequently in endometrioid ovarian tumours, suggesting that these genes may promote differentiation toward this specific subtype. The results presented here provide further evidence for the role of distinct developmental pathways in the progression of epithelial ovarian cancer subtypes.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the TGF β functional pathway in epithelial ovarian carcinoma

Francis-Thickpenny

Richardson

et al. 2001

Br J Cancer

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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.

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?-Catenin mutation and expression analysis in ovarian cancer: Exon 3 mutations and nuclear translocation in 16% of endometrioid tumours

Cited by 123 publications

References 16 publications

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Loss of cell-adhesion molecule complexes in solid pseudopapillary tumor of pancreas

Analysis of the TGF β functional pathway in epithelial ovarian carcinoma

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