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Loss of CADM1 expression is associated with poor prognosis and brain metastasis in breast cancer patients.

ABSTRACT: 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.

SUBMITTER: Wikman H

PROVIDER: S-EPMC4102793 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Loss of CADM1 expression is associated with poor prognosis and brain metastasis in breast cancer patients.

Wikman Harriet H Westphal Laura L Schmid Felicitas F Pollari Sirkku S Kropidlowski Jolanthe J Sielaff-Frimpong Bettina B Glatzel Markus M Matschke Jakob J Westphal Manfred M Iljin Kristiina K Huhtala Heini H Terracciano Luigi L Kallioniemi Anne A Sauter Guido G Müller Volkmar V Witzel Isabell I Lamszus Katrin K Kemming Dirk D Pantel Klaus K

Oncotarget 20140501 10

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-str ...[more]

PMID: 24833255

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Project description:Although keratin 15 (KRT15) has been indicated to be overexpressed in several types of tumor, its role in breast invasive carcinoma (BRCA) has so far remained elusive. The aim of the present study was to explore KRT15 expression in BRCA based on data obtained from The Cancer Genome Atlas and The Genotype-Tissue Expression. KRT15 expression was compared using a Wilcoxon rank-sum test. Functional enrichment analysis was performed to reveal the biological roles and pathways of KRT15. The association between KRT15 expression and immune-cell infiltration was evaluated via single-sample gene set enrichment analysis (ssGSEA). To investigate the relationship between clinicopathological features and KRT15 expression, the prognostic value of KRT15 and other clinical factors was evaluated using Cox regression analysis and Kaplan-Meier (KM) plots. Subgroup prognostic analysis was also performed using forest plots and KM curves. Finally, a tissue microarray was used to assess KRT15 expression in BRCA tissues. KRT15 expression was significantly lower in BRCA tissues compared with that in normal tissues. Functional enrichment analysis suggested that KRT15-related genes were primarily enriched in the transmembrane transporter complex, cornification and ligand-receptor interactions. Increased KRT15 was associated with several tumor-suppressive pathways. ssGSEA revealed that high KRT15 expression was significantly associated with natural killer-cell, B-cell and mast-cell infiltration. Significant associations were observed between low KRT15 expression and advanced stage clinicopathological factors, as well as unfavorable overall survival (OS) and disease-specific survival. Multivariate Cox regression analysis suggested that KRT15 was an independent prognostic factor for OS (P=0.039; hazard ratio, 0.590; 95% CI, 0.358-0.974). Subgroup prognostic analysis demonstrated that low KRT15 was a reliable predictor of poor OS. Immunohistochemistry of a tissue microarray indicated that positive KRT15 expression rates were significantly higher in normal tissues compared with those in the BRCA tissues. In conclusion, low KRT15 expression was significantly associated with poor prognosis in patients with BRCA. Thus, KRT15 may serve an important role in BRCA progression and may be used as a promising prognostic marker for diagnostic and prognostic analyses in patients with BRCA.

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Loss of CADM1 expression is associated with poor prognosis and brain metastasis in breast cancer patients.

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Loss of CADM1 expression is associated with poor prognosis and brain metastasis in breast cancer patients.

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