Loss of Expression and Aberrant Methylation of the CDH1 (E-cadherin) Gene in Breast Cancer Patients from Kashmir

Abstract

Background: Aberrant promoter hypermethylation has been recognized in human breast carcinogenesis as a frequent molecular alteration associated with the loss of expression of a number of key regulatory genes and may serve as a biomarker. The E-cadherin gene (CDH1), mapping at chromosome 16q22, is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections. The aim of our study was to assess the methylation pattern of CDH1 and to correlate it with the expression of E-cadherin, clinicopathological parameters and hormone receptor status in breast cancer patients of Kashmir. Materials and Methods: Methylation specific PCR (MSP) was used to determine the methylation status of CDH1 in 128 invasive ductal carcinomas (IDCs) paired with the corresponding normal tissue samples. Immunohistochemistry was used to study the expression of E-cadherin, ER and PR. Results: CDH1 hypermethylation was detected in 57.8% of cases and 14.8% of normal adjacent controls. Reduced levels of E-cadherin protein were observed in 71.9% of our samples. Loss of E-cadherin expression was significantly associated with the CDH1 promoter region methylation (p<0.05, OR=3.48, CI: 1.55-7.79). Hypermethylation of CDH1 was significantly associated with age at diagnosis (p=0.030), tumor size (p=0.008), tumor grade (p= 0.024) and rate of node positivity or metastasis (p=0.043). Conclusions: Our preliminary findings suggest that abnormal CDH1 methylation occurs in high frequencies in infiltrating breast cancers associated with a decrease in E-cadherin expression. We found significant differences in tumor-related CDH1 gene methylation patterns relevant to tumor grade, tumor size, nodal involvement and age at diagnosis of breast tumors, which could be extended in future to provide diagnostic and prognostic information.

&beta;-Catenin is important for cancer stem cell generation and tumorigenic activity in nasopharyngeal carcinoma

“…However, the expression of E-cadherin was found to be negatively correlated with intracellular β-catenin expression in this study. The inhibitory effect of E-cadherin expression was potentially caused by hypomethylation of E-cadherin gene resulted from activation of signaling pathway, such as JNK pathway [10,31]. The translocation of β-catenin to the nucleus had a validated negative relationship with E-cadherin expression, and the intracellular β-catenin localized in the nucleus of pLKO.1-sh-β-catenin-CNE2 cell was markedly reduced.…”

Chromosome 16q genes CDH1, CDH13 and ADAMTS18 are correlated and frequently methylated in human lymphoma

“…The primer sequences were as follows: CDH1 (CDH1UM sense, 5'-GGT TTG ATT TGA TTG TATTT-3' and CDH1UM antisense, 5'-AAA TAC ATC CCT CAC AAAT-3'; and CDH1M sense, 5'-GGT TCG ATT CGA TCG TATTC-3' and CDH1M antisense, 5'-GAA TAC GTC CCT CGC AAAT-3'); CDH13 (CDH13UM sense, 5'-TTG TGG GGT TGT TTT TTGT-3' and CDH13UM antisense, 5'-AAC TTT TCA TTC ATA CAC ACA-3'; and CDH13M sense, 5'-TCG CGG GGT TCG TTT TTCGC-3' and CDH13M antisense, 5'-GAC GTT TTC ATT CAT ACA CGCG-3'); and ADAMTS18 (ADAMTS18UM sense, 5'-AAA TTG TAG TTT GGT AGG TTT GT-3' and ADAMTS18UM antisense, 5'-CAA CTC CAA ATA AAA ACC ACCA-3'; and ADAMTS18M sense, 5'-TTG TAT TCG GTA GGT TCGC-3' and ADAMTS18M antisense, 5'-ACT CCA AAT AAA AAC CGC CG-3'). Primer sequences were described previously (15,20,21) and were purchased from Eurofins MWG Operon, Inc. (Huntsville, AL, USA). MSP products were visualized under ultraviolet illumination following electrophoresis in 2% agarose gels containing GelRed nucleic acid gel stain (Biotium, Fremont, CA, USA).…”

Effect of genetics, epigenetics and variations in the transcriptional expression of cadherin–E in breast cancer susceptibility

“…En este mismo sentido, en muchos estudios se ha encontrado una disminución significativa de la expresión génica del CDH1 en este tipo de cáncer, independientemente del tipo histológico o molecular, lo cual sugiere la importancia de este gen en la progresión del cáncer de mama (11,12). Con relación a las características histopatológicas del tumor, se encontró una disminución de la expresión en la transcripción del CDH1 en presencia de metástasis.…”

“…En este estudio, se registró una clara diminución de los niveles de expresión en la transcripción del CDH1 en las pacientes con cáncer metastásico, lo cual concuerda con lo encontrado en estudios anteriores, e indica la importancia de la cadherina E en la adhesión celular y en el mantenimiento normal del epitelio que relacionan estrechamente esta molécula con el proceso de metástasis. Asimismo, los altos niveles de expresión del CDH1 se relacionaron con tumores en las etapas iniciales que mantenían su adherencia celular y tenían bajo poder metastásico, mientras que una menor expresión se relacionó con mayores grados del tumor, con la pérdida de la adhesión celular y con un acentuado comportamiento invasivo (2,11,34). Los niveles de expresión en la transcripción del CDH1 no se relacionaron con el estado de la metilación del promotor, posiblemente debido a que otros mecanismos, como las mutaciones génicas, la pérdida de heterocigosidad, los cambios en la estructura de la cromatina y las alteraciones específicas de la transcripción, regulan la expresión del CDH1 (11).…”