Loss of CADM1 expression is associated with poor prognosis and brain metastasis in breast cancer patients
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Harriet Wikman1,*, Laura Westphal1,*, Felicitas Schmid1,2, Sirkku Pollari3, Jolanthe Kropidlowski1, Bettina Sielaff-Frimpong1, Markus Glatzel4, Jakob Matschke4, Manfred Westphal5, Kristiina Iljin3, Heini Huhtala6, Luigi Terracciano7, Anne Kallioniemi8, Guido Sauter9, Volkmar Müller10, Isabell Witzel10, Katrin Lamszus5, Dirk Kemming11, Klaus Pantel1
1 Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
2 Max-Delbrück Center for Molecular Medicine, Berlin, Germany
3 Medical Biotechnology, VTT Technical Research Centre of Finland and Turku Centre for Biotechnology, University of Turku, Turku, Finland
4 Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg-Eppendorf, Hamburg, Germany
5 Department of Neurological Surgery, University Medical Center Hamburg-Eppendorf, Hamburg-Eppendorf, Hamburg, Germany
6 School of Health Sciences, University of Tampere, Tampere, Finland
7 Department of Pathology, Basel University Clinics, Basel, Switzerland
8 Institute of Biomedical Technology, University of Tampere and BioMediTech, Tampere, Fimlab Laboratories, Tampere, Finland
9 Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
10 Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
11 European Laboratory Association, Ibbenbueren, Germany
* These authors share first-authorship
Harriet Wikman, email:
Keywords: breast cancer, brain metastases, CADM1, methylation
Received: January 22, 2014 Accepted: March 16, 2014 Published: March 16, 2014
Breast cancer brain metastases (BCBM) are detected with increasing incidence. In order to detect potential genes involved in BCBM, we first screened for genes down-regulated by methylation in cell lines with site-specific metastatic ability. The expression of five genes, CADM1, SPARC, RECK, TNFAIP3 and CXCL14, which were also found down-regulated in gene expression profiling analyses of BCBM tissue samples, was verified by qRT-PCR in a larger patient cohort. CADM1 was chosen for further down-stream analyses. A higher incidence of CADM1 methylation, correlating with lower expression levels, was found in BCBM as compared to primary BC. Loss of CADM1 protein expression was detected most commonly among BCBM samples as well as among primary tumors with subsequent brain relapse. The prognostic role of CADM1 expression was finally verified in four large independent breast cancer cohorts (n=2136). Loss of CADM1 protein expression was associated with disease stage, lymph node status, and tumor size in primary BC. Furthermore, all analyses revealed a significant association between loss of CADM1 and shorter survival. In multivariate analyses, survival was significantly shorter among patients with CADM1-negative tumors. Loss of CADM1 expression is an independent prognostic factor especially associated with the development of brain metastases in breast cancer patients.
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