Increased claudin‐4 expression is associated with poor prognosis and high tumour grade in breast cancer |
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Authors: | Fiona Lanigan Eadaoin McKiernan Donal J. Brennan Shauna Hegarty Robert C. Millikan Jean McBryan Karin Jirstrom Goran Landberg Finian Martin Michael J. Duffy William M. Gallagher |
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Affiliation: | 1. UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland;2. Department of Pathology and Laboratory Medicine, St. Vincent's University Hospital, Dublin, Ireland;3. UCD School of Medicine and Medical Science, University College Dublin, Dublin, Ireland;4. Institute of Pathology, Queens University, Belfast, United Kingdom;5. Department of Epidemiology, University of North Carolina, Chapel Hill, NC;6. Division of Pathology, Department of Laboratory Medicine, Lund University, Malm? University Hospital, Malm?, Sweden;7. Fax: +353‐1‐2837211. |
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Abstract: | The role of intercellular tight junctions in breast epithelial cells is traditionally thought to be in maintaining polarity and barrier function. However, claudin‐4, a tight junction protein, is overexpressed in breast tumour cells compared to normal epithelial cells, which generally corresponds to a loss in polarity. The aim of this study was to investigate the distribution and potential clinical value of claudin‐4 in breast cancer, and to evaluate its usefulness as a prognostic and predictive biomarker. Expression of claudin‐4 was initially examined by Western blot analysis in a cohort of 88 breast tumours, and was found to correlate positively with tumour grade and negatively with ER. Claudin‐4 expression was then evaluated by immunohistochemistry in a larger cohort of 299 tumours represented on a tissue microarray. Claudin‐4 expression correlated positively with tumour grade and Her2, and negatively with ER. High claudin‐4 expression was also associated with worse breast cancer‐specific survival (p = 0.003), recurrence‐free survival (p = 0.025) and overall survival (p = 0.034). Multivariate analysis revealed that claudin‐4 independently predicted survival in the entire cohort (HR 1.95; 95%CI 1.01–3.79; p = 0.047) and in the ER positive subgroup treated with adjuvant tamoxifen (HR 4.34; 95%CI 1.14–16.53; p = 0.032). This relationship between increased claudin‐4 expression and adverse outcome was validated at the mRNA level in a DNA microarray dataset of 295 breast tumours. We conclude that high levels of claudin‐4 protein are associated with adverse outcome in breast cancer patients, including the subgroup of patients treated with adjuvant tamoxifen. © 2008 Wiley‐Liss, Inc. |
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Keywords: | breast cancer tissue microarrays prognostic biomarkers claudin‐4 tight junctions |
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