Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast
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Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. / Kominsky, Scott L; Argani, Pedram; Korz, Dorian; Evron, Ella; Raman, Venu; Garrett, Elizabeth; Rein, Alan; Sauter, Guido; Kallioniemi, Olli-P; Sukumar, Saraswati.
In: ONCOGENE, Vol. 22, No. 13, 03.04.2003, p. 2021-33.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast
AU - Kominsky, Scott L
AU - Argani, Pedram
AU - Korz, Dorian
AU - Evron, Ella
AU - Raman, Venu
AU - Garrett, Elizabeth
AU - Rein, Alan
AU - Sauter, Guido
AU - Kallioniemi, Olli-P
AU - Sukumar, Saraswati
PY - 2003/4/3
Y1 - 2003/4/3
N2 - Claudins are transmembrane proteins that seal tight junctions, and are critical for maintaining cell-to-cell adhesion in epithelial cell sheets. However, their role in cancer progression remains largely unexplored. Here, we report that Claudin-7 (CLDN-7) expression is lower in invasive ductal carcinomas (IDC) of the breast than in normal breast epithelium, as determined by both RT-PCR (9/10) and Western analysis (6/8). Immunohistochemical (IHC) analysis of ductal carcinoma in situ (DCIS) and IDC showed that the loss of CLDN-7 expression correlated with histological grade in both DCIS (P<0.001, n=38) and IDC (P=0.014, n=31), occurring predominantly in high-grade (Nuclear and Elston grade 3) lesions. Tissue array analysis of 355 IDC cases further confirmed the inverse correlation between CLDN-7 expression and histological grade (P=0.03). This pattern of expression is consistent with the biological function of CLDN-7, as greater discohesion is typically observed in high-grade lesions. In line with this observation, by IHC analysis, CLDN-7 expression was lost in the vast majority (13/17) of cases of lobular carcinoma in situ, which is defined by cellular discohesion. In fact, inducing disassociation of MCF-7 and T47D cells in culture by treating with HGF/scatter factor resulted in a loss of CLDN-7 expression within 24 h. Silencing of CLDN-7 expression correlated with promoter hypermethylation as determined by methylation-specific PCR (MSP) and nucleotide sequencing in breast cancer cell lines (3/3), but not in IDCs (0/5). In summary, these studies provide insight into the potential role of CLDN-7 in the progression and ability of breast cancer cells to disseminate.
AB - Claudins are transmembrane proteins that seal tight junctions, and are critical for maintaining cell-to-cell adhesion in epithelial cell sheets. However, their role in cancer progression remains largely unexplored. Here, we report that Claudin-7 (CLDN-7) expression is lower in invasive ductal carcinomas (IDC) of the breast than in normal breast epithelium, as determined by both RT-PCR (9/10) and Western analysis (6/8). Immunohistochemical (IHC) analysis of ductal carcinoma in situ (DCIS) and IDC showed that the loss of CLDN-7 expression correlated with histological grade in both DCIS (P<0.001, n=38) and IDC (P=0.014, n=31), occurring predominantly in high-grade (Nuclear and Elston grade 3) lesions. Tissue array analysis of 355 IDC cases further confirmed the inverse correlation between CLDN-7 expression and histological grade (P=0.03). This pattern of expression is consistent with the biological function of CLDN-7, as greater discohesion is typically observed in high-grade lesions. In line with this observation, by IHC analysis, CLDN-7 expression was lost in the vast majority (13/17) of cases of lobular carcinoma in situ, which is defined by cellular discohesion. In fact, inducing disassociation of MCF-7 and T47D cells in culture by treating with HGF/scatter factor resulted in a loss of CLDN-7 expression within 24 h. Silencing of CLDN-7 expression correlated with promoter hypermethylation as determined by methylation-specific PCR (MSP) and nucleotide sequencing in breast cancer cell lines (3/3), but not in IDCs (0/5). In summary, these studies provide insight into the potential role of CLDN-7 in the progression and ability of breast cancer cells to disseminate.
KW - Breast/cytology
KW - Breast Neoplasms/chemistry
KW - Carcinoma, Ductal, Breast/chemistry
KW - Carcinoma, Intraductal, Noninfiltrating/chemistry
KW - Carcinoma, Lobular/chemistry
KW - Cell Adhesion/drug effects
KW - Cells, Cultured/chemistry
KW - Claudins
KW - DNA Methylation
KW - Epithelial Cells/chemistry
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Gene Silencing
KW - Hepatocyte Growth Factor/pharmacology
KW - Humans
KW - Membrane Proteins/biosynthesis
KW - Neoplasm Invasiveness/genetics
KW - Neoplasm Proteins/biosynthesis
KW - Polymerase Chain Reaction
KW - Promoter Regions, Genetic
KW - RNA, Messenger/analysis
KW - RNA, Neoplasm/analysis
KW - Sequence Analysis, DNA
KW - Severity of Illness Index
KW - Tight Junctions/chemistry
KW - Tumor Cells, Cultured/chemistry
U2 - 10.1038/sj.onc.1206199
DO - 10.1038/sj.onc.1206199
M3 - SCORING: Journal article
C2 - 12673207
VL - 22
SP - 2021
EP - 2033
JO - ONCOGENE
JF - ONCOGENE
SN - 0950-9232
IS - 13
ER -
