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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

  1. Author:
    Kominsky, S. L.
    Argani, P.
    Korz, D.
    Evron, E.
    Raman, V.
    Garrett, E.
    Rein, A.
    Sauter, G.
    Kallioniemi, O. P.
    Sukumar, S.

  2. Author Address

    Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Breast Canc Program, BBCRB Room 410,1650 Orleans St, Baltimore, MD 21231 USA Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Breast Canc Program, Baltimore, MD 21231 USA Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21231 USA Johns Hopkins Univ, Sch Med, Dept Oncol Biostat, Baltimore, MD 21231 USA Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21231 USA NCI, HIV Drug Resistance Program, Frederick, MD 21072 USA NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA Univ Basel, Inst Pathol, CH-4003 Basel, Switzerland Sukumar S Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Breast Canc Program, BBCRB Room 410,1650 Orleans St, Baltimore, MD 21231 USA
    1. Year: 2003
  2. Journal: Oncogene
    1. 22
    2. 13
    3. Pages: 2021-2033
  4. Type of Article: Article
  1. Abstract:

    Claudius 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 (IDS) and IDC showed that the loss of CLDN-7 expression correlated with histological grade in both MIS (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.

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