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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

Oncogene volume 22, pages 2021–2033 (2003)Cite this article

Abstract

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.

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Abbreviations

CLDN:

Claudin

IDC:

invasive ductal carcinoma

RT–PCR:

reverse transcription–PCR

IHC:

immunohistochemical analysis

DCIS:

ductal carcinoma in situ

LCIS:

lobular carcinoma in situ

HGF/scatter factor:

hepatocyte growth factor/scatter factor

KLH:

keyhole limpet hemocyanin

MSP:

methylation-specific PCR

DAB:

3 3′-diaminobenzamidine

GAPDH:

glyceraldehyde phosphate dehydrogenase

5-aza-dC:

5′-aza-2′-deoxycytidine

HMEC:

human mammary epithelial cells

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Acknowledgements

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.

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Author notes

  1. Ella Evron

    Present address: Rabin Medical Center, Petach Tikva, Israel

Authors and Affiliations

  1. Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, 21231, MD, USA

    Scott L Kominsky, Dorian Korz, Ella Evron & Saraswati Sukumar

  2. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, 21231, MD, USA

    Pedram Argani

  3. Department of Oncology-Biostatistics, Johns Hopkins University School of Medicine, Baltimore, 21231, MD, USA

    Elizabeth Garrett

  4. Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, 21231, MD, USA

    Venu Raman

  5. HIV Drug Resistance Program, National Cancer Institute-Frederick, Frederick, 21072-1201, MD, USA

    Alan Rein

  6. Institute of Pathology, University of Basel, Basel, 4003, Switzerland

    Guido Sauter

  7. Cancer Genetics Branch, NHGRI, NIH, Bethesda, 20892, MD, USA

    Olli-P Kallioniemi

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  1. Scott L Kominsky
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Correspondence to Saraswati Sukumar.

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Kominsky, S., Argani, P., Korz, D. et al. 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 22, 2021–2033 (2003). https://doi.org/10.1038/sj.onc.1206199

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