Abstract
Introduction ECRG4/C2ORF40 is a potential tumor suppressor gene (TSG) recently identified in esophageal carcinoma. Its expression, gene copy number and prognostic value have never been explored in breast cancer.MethodsUsing DNA microarray and array-based comparative genomic hybridization (aCGH), we examined ECRG4 mRNA expression and copy number alterations in 353 invasive breast cancer samples and normal breast (NB) samples. A meta-analysis was done on a large public retrospective gene expression dataset (n = 1,387) in search of correlations between ECRG4 expression and histo-clinical features including survival.Results ECRG4 was underexpressed in 94.3% of cancers when compared to NB. aCGH data revealed ECRG4 loss in 18% of tumors, suggesting that DNA loss is not the main mechanism of underexpression. Meta-analysis showed that ECRG4 expression was significantly higher in tumors displaying earlier stage, smaller size, negative axillary lymph node status, lower grade, and normal-like subtype. Higher expression was also associated with disease-free survival (DFS; HR = 0.84 [0.76–0.92], p = 0.0002) and overall survival (OS; HR = 0.72 [0.63–0.83], p = 5.0E-06). In multivariate analysis including the other histo-clinical prognostic features, ECRG4 expression remained the only prognostic factor for DFS and OS.ConclusionsOur data suggest that ECRG4 is a candidate TSG in breast cancer, the expression of which may help improve the prognostication. If functional analyses confirm this TSG role, restoring ECRG4 expression in the tumor may represent a promising therapeutic approach.
Highlights
Esophageal cancer-related gene 4 (ECRG4)/C2ORF40 is a potential tumor suppressor gene (TSG) recently identified in esophageal carcinoma
To attempt exploring the biological pathways linked to ECRG4 expression, we identified genes correlated with ECRG4 mRNA levels using Significance Analysis of Microarrays (SAM) [21] in our own data set
ECRG4 mRNA expression in breast cancer We first analyzed expression data generated in our laboratory by using Affymetrix microarrays from 357 mammary samples including 353 pre-treatment primary cancers and 4 normal breast (NB) samples
Summary
ECRG4/C2ORF40 is a potential tumor suppressor gene (TSG) recently identified in esophageal carcinoma. Gene copy number and prognostic value have never been explored in breast cancer. Despite the mass screening and multidisciplinary therapeutic progresses, a substantial number of patients (,25%) die from metastatic disease. Breast cancer is a complex disease characterized by the accumulation of multiple molecular alterations, genetic and epigenetic, which disturb the expression of genes controlling critical regulatory processes. Efforts have been directed at the identification of genes that play important roles in mammary oncogenesis and metastatic processes and that could represent new therapeutic and/or prognostic targets. Key genes have been identified, including oncogenes encoding hormone receptors (ER and PR) and tyrosine kinase receptors (ERBB2, EGFR), and tumor suppressor genes (TSG) such as TP53, BRCA1, and BRCA2. Our molecular understandings of breast cancer, together with clinical benefits for patients, remain limited
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