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

Oncogene. 2003 Apr 3;22(13):2021-33. doi: 10.1038/sj.onc.1206199.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Breast / cytology
  • Breast / metabolism*
  • Breast Neoplasms / chemistry*
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / chemistry*
  • Carcinoma, Ductal, Breast / pathology
  • Carcinoma, Intraductal, Noninfiltrating / chemistry*
  • Carcinoma, Intraductal, Noninfiltrating / pathology
  • Carcinoma, Lobular / chemistry*
  • Carcinoma, Lobular / pathology
  • Cell Adhesion / drug effects
  • Cells, Cultured / chemistry
  • Cells, Cultured / drug effects
  • Claudins
  • DNA Methylation
  • Epithelial Cells / chemistry
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Hepatocyte Growth Factor / pharmacology
  • Humans
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology
  • Neoplasm Invasiveness / genetics*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / deficiency*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic
  • RNA, Messenger / analysis
  • RNA, Neoplasm / analysis
  • Sequence Analysis, DNA
  • Severity of Illness Index
  • Tight Junctions / chemistry*
  • Tumor Cells, Cultured / chemistry
  • Tumor Cells, Cultured / drug effects


  • CLDN7 protein, human
  • Claudins
  • Membrane Proteins
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • Hepatocyte Growth Factor