Low frequency of E-cadherinalterations in familial breast cancer

Salahshor, Sima; Lei, Hetian; Huo, Huagang; Kristensen, Vessela N.; Loman, Niklas; Sjöberg-Margolin, Sara; Borg, Åke; Børresen-Dale, Anne Lise; Vořechovský, Igor; Lindblom, Annika

doi:10.1186/bcr295

Cited by 42 publications

(30 citation statements)

References 33 publications

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“…Among the various IDC types, negative expression was characteristically observed in both the cases of IDC with comedo necrosis. Salahshor et al 32 reported a germline E-CD alteration (Aa592Thr) in cases of IDCs with comedo necrosis, which was considered to be responsible for phenotypic divergence of this variant from other IDC types, thereby forming an underlying reason for its negative expression in the present study. This further substantiates aggressive behavior of this tumor type.…”

Section: Discussionmentioning

confidence: 48%

Expression of E-Cadherin in breast carcinomas and its association with other biological markers — a prospective study

Chintamani

Rekhi

Bansal

et al. 2010

Indian J Surg Oncol

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Context E-cadherin (E-CD) is an important cell adhesion molecule in normal epithelial cells and has been shown to be an invasion tumor suppressor gene. Materials and methods Various clinicopathological parameters like age, family history, tumor stage, histological grade, lymph node status and other biological markers were also analyzed. Present study reveals E-CD expression in 65 cases of breast cancer including 41 (63%) cases of pure infiltrating ductal carcinoma (IDC), 11 (16.9%) of pure infiltrating lobular carcinoma (ILC); another 10 (15.3%) of mixed ductal/lobular type, and remaining 3 (4.6%) miscellaneous types.Results Negative E-CD expression was noticed more in advancing age groups (P = 0.01). About 59.2% cases showing negative E-CD expression had family history of breast and/or other cancers. E-CD expression was found significantly higher in cases of pure IDC (55.5%) than in pure ILC cases (18.1%) (P = 0.04). Eleven (68.7%) of the total 16 high-grade IDC cases, revealed negative expression. Both cases of comedo carcinoma revealed negative expression. Three (30%) out of 10 mixed cases revealed negative expression in both ductal and lobular areas, while in remaining 7 cases, positvity was seen in ductal areas only. Invasive cribriform and medullary carcinoma revealed a stronger expression, while negative staining was observed in sweat gland carcinoma. E-CD re-expression was noticed in lymph node tumor deposits. A direct association of E-CD expression with ER expression and an inverse association with that of p53 were also observed (P = 0.001), (P = 0.04). Conclusions E-CD expression is useful, but limited, in differentiating IDCs from ILCS. Its negative expression correlates with certain poor prognostic parameters reflecting its use as a marker for invasive cancers. It re-expresses at metastatic sites.

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Section: Discussionmentioning

confidence: 48%

Expression of E-Cadherin in breast carcinomas and its association with other biological markers — a prospective study

Chintamani

Rekhi

Bansal

et al. 2010

Indian J Surg Oncol

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“…[18][19][20][21] Abnormal Ecadherin in breast carcinomas has been associated mainly with E-cadherin promoter methylation and very few mutations in the gene have been reported. 22,23 Previous studies showed that decreased immunoreactivity of E-cadherin statistically correlated with the presence of lymph node metastases in esophageal squamous cell carcinoma, and loss of intercellular adhesion activates a transition from low-to high-grade squamous cell carcinoma, thus indicating an important role for E-cadherin as a prognostic marker in the progression of tumors. 24,25 Increased expression of the 80 kDa fragment of E-cadherin in metastatic prostate cancer in association with increased levels of several metalloproteinases, which are believed to be responsible for cleavage of short E-cadherin fragment from the full-length Ecadherin, are suggested to induce tumor progression in this tumor.…”

Section: Discussionmentioning

confidence: 99%

Frequent accumulation of nuclear E-cadherin and alterations in the Wnt signaling pathway in esophageal squamous cell carcinomas

et al. 2008

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Esophageal squamous cell carcinoma is frequently associated with poor prognosis, as a result of high levels of lymph node metastasis. So far, very few genetic abnormalities have been associated with this disease, and its molecular etiology remains largely unknown. To assess whether the Wnt pathway contributes to esophageal squamous cell carcinoma, we characterized the expression and subcellular localization of the key Wnt signaling components in all 30 cases of esophageal squamous cell carcinomas analyzed. We found abnormal expression and/or localization in glycogen synthase kinase-3 a/b (34%), Axin2 (48%), a-catenin (31%), MYC (73%) and cyclin D1 in 46% of cases. Only 13% of tumors showed nuclear accumulation of b-catenin. By contrast, 60% showed nuclear expression of E-cadherin using an antibody that recognizes the cytoplasmic domain of E-cadherin. When the same tumors were stained with antibody raised against the extracellular domain of E-cadherin, the expression was lost. A direct correlation was found between nuclear E-cadherin and the increased nuclear cyclin D1, one of the AP-1 target genes in these tumors. By transfection experiments, the cytoplasmic portion of E-cadherin was found to activate the AP-1 transcription factor pathway and induced cyclin D1 promoter activity, but b-catenin/Tcf transcription activity was unaffected. Nuclear expression of E-cadherin was also detected in tumors other than squamous cell carcinoma, including pancreatic and colon cancers, albeit at lower frequency. Nuclear accumulation of a portion of E-cadherin in esophageal squamous cell carcinoma and the other types of tumors indicates that, in addition to the previously implicated tumor suppressor activity of E-cadherin, modified forms of this glycoprotein might also play a role in growth promotion. Keywords: Wnt signaling; esophageal squamous cell carcinomas; pancreatic cancer; colon cancer; E-cadherin Esophageal cancer is one of the deadliest but least studied forms of cancer and the sixth ranking cause of death from cancer in North America. It shows a varied geographical distribution and very poor survival rates. 1 Esophageal cancer accounts for 5% of all gastrointestinal cancers, and the overall number of new cases each year is steadily increasing. 2 Esophageal cancer can be divided into squamous cell carcinomas and adenocarcinomas. So far, very few genetic abnormalities have directly been linked to esophageal carcinogenesis. In this study, we sought to examine the expression and localization of the key components of the Wnt signaling pathway that have previously been shown to play important roles in colorectal, breast, stomach and prostate cancer. Wnt signaling regulates cell growth, motility and differentiation. Upon binding to their receptor, specific Wnt ligands trigger phosphorylation of LRP5/6 (low density lipoprotein) by glycogen synthase kinase-3 (GSK3a/b) and casein kinase-1 (CK1g), which distances Axin (Axin1 and Axin2) from the b-catenin destruction-complex. [3][4][5][6] As a result, the b-catenin is stabilized a...

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“…In one of the families the occurrence of lung and rectal cancer was reported , but the detailed history of the other family was not described (Moran et al, 2005). A somatic 49-2A>C mutation has been shown in a breast tumour of both ductal and lobular histology (Salahshor et al, 2001).…”

Section: Familymentioning

confidence: 99%

Identification of seven novel germline mutations in the human E-cadherin (CDH1) Gene

Humar

Weber

et al. 2007

Hum. Mutat.

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Hereditary diffuse gastric cancer (HDGC) is a cancer predisposition syndrome caused by germline mutation of the gene encoding the tumour-suppressor E-cadherin (CDH1). We describe the search for CDH1 mutations in 36 new diffuse gastric cancer families. All 16 CDH1 exons, neighbouring intronic sequence and an essential promoter region were screened by DNA sequencing. We detected nine different mutations, seven of which were novel. Of the seven novel mutations, five were identified in families who met the IGCLC clinical criteria for HDGC. Two mutations resulted in a premature stop codon and truncation of the protein. Three mutations affected splice sites; two of the splice-site mutations were shown by RT-PCR to disturb normal CDH1 splicing, while the third splicesite mutation was present in two unrelated HDGC families. The remaining two mutations resulted in amino acid substitutions and impaired the ability of E-cadherin protein to form cellular aggregates and suppress invasion in vitro. Together with the occurrence of extragastric tumours such as lobular breast and colorectal cancer, these findings further extend the types of CDH1 mutations and the spectrum of tumours associated with HDGC.

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Low frequency of E-cadherinalterations in familial breast cancer

Cited by 42 publications

References 33 publications

Expression of E-Cadherin in breast carcinomas and its association with other biological markers — a prospective study

Expression of E-Cadherin in breast carcinomas and its association with other biological markers — a prospective study

Frequent accumulation of nuclear E-cadherin and alterations in the Wnt signaling pathway in esophageal squamous cell carcinomas

Identification of seven novel germline mutations in the human E-cadherin (CDH1) Gene

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