P-Cadherin Overexpression Is an Indicator of Clinical Outcome in Invasive Breast Carcinomas and Is Associated with <i>CDH3</i> Promoter Hypomethylation

Paredes, Joana; Albergaria, André; Oliveira, João Tiago; Jerónimo, Carmen; Milanezi, Fernanda; Schmitt, Fernando

doi:10.1158/1078-0432.ccr-05-0059

Cited by 234 publications

(212 citation statements)

References 38 publications

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“…Figure 1b shows that cell lines with higher levels of P-cadherin expression revealed an increased ability to invade through Matrigel. More importantly, these results are in agreement with what has been described in invasive primary breast tumours, showing the clinical relevance of P-cadherin expression in the diagnosis and prognosis of patients with aggressive mammary carcinomas (Peralta Soler et al, 1999;Paredes et al, 2005).…”

Section: P-cadherin Overexpression In Wild-type E-cadherin Breast Cansupporting

confidence: 90%

“…Previous studies have shown that P-cadherin expression in breast carcinomas is able to identify a subgroup of lesions with a more aggressive behaviour and poor patient survival (Peralta Soler et al, 1999;Gamallo et al, 2001;Paredes et al, 2002Paredes et al, , 2004Paredes et al, , 2005Paredes et al, , 2008. Similar associations between P-cadherin expression and poor prognosis are described in other cancer models, namely endometrial, cervical, gastric and pancreatic carcinomas (Stefansson et al, 2004;Longatto Filho et al, 2005;Taniuchi et al, 2005).…”

Section: Discussionmentioning

confidence: 66%

“…In contrast, these tumours overexpress P-cadherin, maintaining the normal E-cadherin expression (Paredes et al, , 2008. In clinical terms, these P-cadherin-overexpressing tumours present high histological grade, with decreased cell polarity, aggressive behaviour and worse patient survival (Peralta Soler et al, 1999;Gamallo et al, 2001;Paredes et al, 2002Paredes et al, , 2005. On the basis of these observations, we aimed to understand how P-cadherin, in an E-cadherin wild-type background, could influence the behaviour of these tumours.…”

Section: Introductionmentioning

confidence: 99%

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Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells

et al. 2009

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Cell-cell adhesion is an elementary process in normal epithelial cellular architecture. Several studies have shown the role mediated by cadherins in this process, besides their role in the maintenance of cell polarity, differentiation and cell growth. However, during tumour progression, these molecules are frequently altered. In breast cancer, tumours that overexpress P-cadherin usually present a high histological grade, show decreased cell polarity and are associated with worse patient survival. However, little is known about how this protein dictates the very aggressive behaviour of these tumours. To achieve this goal, we set up two breast cancer cell models, where P-cadherin expression was differently modulated and analysed in terms of cell invasion, motility and migration. We show that P-cadherin overexpression, in breast cancer cells with wild-type E-cadherin, promotes cell invasion, motility and migration. Moreover, we found that the overexpression of P-cadherin induces the secretion of matrix metalloproteases, specifically MMP-1 and MMP-2, which then lead to P-cadherin ectodomain cleavage. Further, we showed that soluble P-cadherin fragment is able to induce in vitro invasion of breast cancer cells. Overall, our results contribute to elucidate the mechanism underlying the invasive behaviour of P-cadherin expressing breast tumours.

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Section: P-cadherin Overexpression In Wild-type E-cadherin Breast Cansupporting

confidence: 90%

Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

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Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells

et al. 2009

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“…Several studies have revealed that there is a good inverse correlation between methylation and gene expression. overexpression of P450 1B1 was regulated by hypomethylation in prostate cancer (25), while P-cadherin mrna expression in invasive breast carcinomas was associated with the hypomethylation of the cdH3 promoter (26). These reports suggest that the hypomethylation of specific oncogene promoters may play an important role in tumorigenesis.…”

Section: Bmentioning

confidence: 80%

Fascin overexpression is regulated by the transactivation of the promoter but not by its hypomethylation in esophageal squamous cell carcinoma

Hou

Guo²,

Xie³

et al. 2009

Mol Med Rep

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Abstract. Fascin 1 (fascin) is known to be overexpressed in esophageal squamous cell carcinoma (eScc); however, the mechanisms of this overexpression are unclear. in this study, the FScn1 core promoter was isolated and the transcriptional regulatory mechanism of fascin overexpression in eScc was investigated. By combining the use of progressive 5' deletions and dual-luciferase reporter assays, the FScn1 core promoter was identified within the -74/-41 region in esophageal carcinoma EC109 cells harboring a GC box and a composite CRE/AP-1 binding site. Further analysis demonstrated that only the Gc box was essential for transcription. no methylated cpG sites were found within the FScn1 promoter in normal and tumor cells or tissues examined by methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS), which suggested that hypomethylation did not contribute to the overexpression of fascin in ESCC. Furthermore, the region of +168/+2838 was found to inhibit promoter activity. additional BGS analysis indicated that the region of +560/+859 (in exon 1) was hypermethylated in normal and tumor cells or tissues. unexpectedly, demethylation did not eliminate the suppression, suggesting that a silencer caused this suppression, and not dna methylation in exon 1. Taken together, the results indicate that fascin overexpression in eScc is regulated by the transactivation of the fascin promoter, but not by its hypomethylation. IntroductionFascin 1 (fascin), a 55-kda globular actin-bundling protein (1), is expressed in specific tissues and cells (2). In tissues such as brain and spleen, fascin is abundantly expressed, while at the cellular level it is observed mainly in neuronal and glial cells and microcapillary endothelial cells, as well as in antigenpresenting dendritic cells (dcs) (3-6).Fascin is expressed at low levels or is absent in normal epithelia, but is overexpressed in many human carcinomas (7). Fascin overexpression is correlated with poor patient prognosis in certain tumors, such as non-small-cell lung cancer and gastric, breast and oesophageal carcinomas (8-11). in esophageal squamous cell carcinoma (eScc), it has been shown that the up-regulation of fascin occurs during the early stages of malignant transformation and is correlated with lymph-node metastasis (12). Hashimoto et al reported that in ESCC the infiltrative margins tended to stain most strongly for fascin (11), while a report from Xie et al revealed that fascin was localized in the membrane protrusion of eScc cells, and that the down-regulation of fascin resulted in the suppression of cell proliferation and invasiveness (13). These findings strongly suggest that the overexpression of fascin plays an important role in invasion and metastasis in eScc. However, the mechanisms by which fascin is up-regulated in carcinoma cells remain unclear.Human fascin is encoded by the FScn1 gene located at chromosome 7p22, which contains a 9-kb-intron 1 and another three introns. FScn1 mrna consists of a 121-bp 5' untranslated region, a 1174-bp 3' untranslated ...

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“…Doubledistilled water was used instead of DNA as the blank control. Assessment of methylation status for the cases was as follows: those showing products amplified by methylated primers were considered methylated and those showing only products amplified by unmethylated primers were considered unmethylated (27,28).…”

Section: Methodsmentioning

confidence: 99%

Effect of the methylenetetrahydrofolate reductase gene C677T polymorphism on C-erbB-2 methylation status and its association with cancer

Jin

Lü²,

Ge³

et al. 2009

Mol Med Rep

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Abstract. Methylation abnormalities of cancer-related genes are recognized to play an important role in carcinogenesis. Methylenetetrahydrofolate reductase (MTHFR) regulates DNA methylation by affecting synthesis of S-adenosylmethionine, which is a universal methyl donor for methylation reactions. MTHFR gene polymorphisms that affect enzymatic activity may be associated with DNA methylation and cancer susceptibility. In the present study, we investigated the MTHFR C677T polymorphism in 247 cancer patients and 100 healthy subjects using PCR-RFLP, as well as the methylation status of the CpG island in the promoter region of the C-erbB-2 oncogene in 247 tumor and matched adjacent tissue samples using methylation-specific PCR. The results revealed that the methylation rate of the C-erbB-2 gene was significantly lower in the tumor tissues than in the matched adjacent tissues (43.3 vs. 69.2%, P=0.000). No correlation was observed between the methylation patterns of C-erbB-2 in tumor tissues and the clinicopathological characteristics of the patients. The frequency of the MTHFR gene 677 T allele was significantly higher in cancer patients than in the healthy subjects, and the combined variant genotypes (677CT+TT) significantly increased the risk of developing cancer (OR=1.619, 95% CI 1.012-2.588, P=0.043). Among the cancer patients, the methylation rate of the C-erbB-2 gene was higher in individuals with the CC genotype than in those with the CT/TT genotype (50.0 vs. 39.4%). This difference was not significant (P=0.103). However, a significant difference was found in patients with breast cancer (P=0.008). In conclusion, the C-erbB-2 promoter CpG island was hypomethylated in cancer patients, and the MTHFR 677 CT/TT genotype increased the risk of developing the disease. Moreover, in breast cancer patients, the MTHFR gene C677T polymorphism had an effect on the methylation status of the C-erbB-2 gene.

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P-Cadherin Overexpression Is an Indicator of Clinical Outcome in Invasive Breast Carcinomas and Is Associated with CDH3 Promoter Hypomethylation

Cited by 234 publications

References 38 publications

Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells

Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells

Fascin overexpression is regulated by the transactivation of the promoter but not by its hypomethylation in esophageal squamous cell carcinoma

Effect of the methylenetetrahydrofolate reductase gene C677T polymorphism on C-erbB-2 methylation status and its association with cancer

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