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Open Access Highly Accessed Research article

The ubiquitin-like molecule interferon-stimulated gene 15 (ISG15) is a potential prognostic marker in human breast cancer

Nuran Bektas1, Erik Noetzel1, Jürgen Veeck1, Michael F Press2, Glen Kristiansen3, Amjad Naami1, Arndt Hartmann4, Arno Dimmler4, Matthias W Beckmann5, Ruth Knüchel1, Peter A Fasching5 and Edgar Dahl1*

Author Affiliations

1 Department of Pathology, University Hospital of the RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany

2 Department of Pathology, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA

3 Department of Pathology, University Hospital Zürich, Schmelzbergstrasse 12, 8091 Zürich, Switzerland

4 Department of Pathology, University Hospital Erlangen, Krankenhausstrasse 12, 91054 Erlangen, Germany

5 Department of Gynaecology, University Hospital Erlangen, Universitätsstrasse 21-23, 91054 Erlangen, Germany

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Breast Cancer Research 2008, 10:R58  doi:10.1186/bcr2117

Published: 15 July 2008

Abstract

Introduction

ISG15 is an ubiquitin-like molecule that is strongly upregulated by type I interferons as a primary response to diverse microbial and cellular stress stimuli. However, alterations in the ISG15 signalling pathway have also been found in several human tumour entities. To the best of our knowledge, in the current study we present for the first time a systematic characterisation of ISG15 expression in human breast cancer and normal breast tissue both at the mRNA and protein level.

Method

Using semiquantitative real-time PCR, cDNA dot-blot hybridisation and immunohistochemistry, we systematically analysed ISG15 expression in invasive breast carcinomas (n = 910) and normal breast tissues (n = 135). ISG15 protein expression was analysed in two independent cohorts on tissue microarrays; in an initial evaluation set of 179 breast carcinomas and 51 normal breast tissues; and in a second large validation set of 646 breast carcinomas and 10 normal breast tissues. In addition, a collection of benign and malignant mammary cell lines (n = 9) were investigated for ISG15 expression.

Results

ISG15 was overexpressed in breast carcinoma cells compared with normal breast tissue, both at the RNA and protein level. Recurrence-free (p = 0.030), event-free (p = 0.001) and overall (p = 0.001) survival analyses showed a significant correlation between ISG15 overexpression and unfavourable prognosis.

Conclusion

Therefore, ISG15 may represent a novel breast tumour marker with prognostic significance and may be helpful in selecting patients for and predicting response to the treatment of human breast cancer.