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
N1 - Funding Information:
We gratefully acknowledge Leslie Meszler at the Cell Imaging Core Facility, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, for expert assistance with confocal microscopy. We thank Dr Vimla Band, Dr Sigmund A Weitzman, Dr Martha Stampfer, Dr Steven Ethier, Dr Birunthi Niranjan, and Dr Lakjaya Buluwela for their generous gift of breast cells of normal and cancer origin. We are also thankful to the members of the Sukumar laboratory for useful advice and discussions. This work was supported by PHHS Grants SPORE P50 CA88843 (to S Sukumar), and DAMD17-01-1-0285 (to S Sukumar) and BC010495 (to SL Kominsky) from the US Army Medical Research and Materiel Command.
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 24h. 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 24h. 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 cancer
KW - Claudin-7
KW - Methylation
KW - Tight junction
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U2 - 10.1038/sj.onc.1206199
DO - 10.1038/sj.onc.1206199
M3 - Article
C2 - 12673207
AN - SCOPUS:0037417428
SN - 0950-9232
VL - 22
SP - 2021
EP - 2033
JO - Oncogene
JF - Oncogene
IS - 13
ER -