Biomarker discovery to improve prediction of breast cancer survival: using gene expression profiling, meta-analysis, and tissue validation

Abstract

PurposeBreast cancer is the leading cause of cancer death worldwide in women. The molecular mechanism for human breast cancer is unknown. Gene microarray has been widely used in breast cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis survival. So far, the valuable multigene signatures in clinical practice are unclear, and the biological importance of individual genes is difficult to detect, as the described signatures virtually do not overlap. Early prognosis of this disease, breast invasive ductal carcinoma (IDC) and breast ductal carcinoma in situ (DCIS), is vital in breast surgery.MethodsThus, this study reports gene expression profiling in large breast cancer cohorts from Gene Expression Omnibus, including GSE29044 (N=138) and GSE10780 (N=185) test series and four independent validation series GSE21653 (N=266), GSE20685 (N=327), GSE26971 (N=276), and GSE12776 (N=204). Significantly differentially expressed genes in human breast IDC and breast DCIS were detected by transcriptome microarray analysis.ResultsWe created a set of three genes (MAMDC2, TSHZ2, and CLDN11) that were significantly correlated with disease-free survival of breast cancer patients using a univariate Cox regression model (significance level P<0.01) in a meta-analysis. Based on the risk score of the three genes, the test series patients could be separated into low-risk and high-risk groups with significantly different survival times. This signature was validated in the other three cohorts. The prognostic value of this three-gene signature was confirmed in the internal validation series and another four independent breast cancer data sets. The prognostic impact of one of the three genes, CLDN11, was confirmed by immunohistochemistry. CLDN11 was significantly overexpressed in human breast IDC as compared with normal breast tissues and breast DCIS.ConclusionUsing novel gene expression profiling together with a meta-analysis validation approach, we have identified a three-gene signature with independent prognostic impact. Furthermore, CLDN11 may offer a biomarker to predict prognosis as well as a new target for prognostic and therapeutic intervention for human breast IDC.

Prognostic Genes of Breast Cancer Identified by Gene Co-expression Network Analysis

“…High CXCR4 levels were associated with lymph node metastasis and distant metastasis ( 15 ). Despite the substantial improvements in the treatment of breast cancer, to date, the ability to treat the advanced ones is still limited due to the lack of precise molecular targets for breast cancer ( 16 ). Therefore, it is important to explore the molecule mechanisms involved in the occurrence and development of breast cancer.…”

The Clinical Signification of Claudin-11 Promoter Hypermethylation for Laryngeal Squamous Cell Carcinoma

“…Previous quantitative reviews have shown that the expression of CLDN11 significantly correlated with survival of breast cancer patients [ 46 ]. Multiple factors regulate gene transcription, and aberrant DNA methylation is one of the most important mechanisms [ 47 ].…”

Suppression of human breast cancer cells by tectorigenin through downregulation of matrix metalloproteinases and MAPK signaling in�vitro

“…Although the current first-line therapies for breast cancer, which include surgery, radiotherapy and chemotherapy, have allowed for great achievements in clinical control, poor prognosis and serious side effects remain and must be addressed (19)(20)(21)(22)(23)(24). Another primary problem of treatments for breast cancer is a high incidence of failure and relapse with drug resistance (4-6).…”