Abstract
BackgroundTamoxifen is the first-line hormone therapy for estrogen receptor alpha positive (ERα+) breast cancer. However, about 40% of patients with ERα + breast cancer who receive tamoxifen therapy eventually develop resistance resulting in a poor prognosis. The aim of this study was to mine available data sets in the Gene Expression Omnibus (GEO) database, including in vitro (cell lines) and in vivo (tissue samples), and to identify all miRNAs associated with tamoxifen resistance (TamR) in breast cancer. Secondly, this study aimed to predict the key gene regulatory networks of newly found TamR-related miRNAs and evaluate the potential role of the miRNAs and targets as potential prognosis biomarkers for breast cancer patients.ResultMicroarray data sets from two different studies were used from the GEO database: 1. GSE66607: miRNA of MCF-7 TamR cells; 2. GSE37405: TamR tissues. Differentially expressed microRNAs (miRNAs) were identified in both data sets and 5 differentially expressed miRNAs were found to overlap between the two data sets. Profiles of GSE37405 and data from the Kaplan-Meier Plotter Database (KMPD) along with Gene Expression Profiling Interactive Analysis (GEPIA) were used to reveal the relationship between these 5 miRNAs and overall survival. The results showed that has-miR-542-5p was the only miRNA associated with overall survival of ERα + breast cancer patients who received adjuvant tamoxifen. Targets of has-miR-542-5p were predicted by miRanda and TargetScan, and the mRNA expression of the three 3 target gene, Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Beta (YWHAB), Lymphocyte Antigen 9 (LY9), and Secreted Frizzled Related Protein 1 (SFRP1) were associated with overall survival in 2 different databases. Copy-number alterations (CNAs) of SFRP1 confer survival disadvantage to breast cancer patients and alter the mRNA expression of SFRP1 in cBioPortal database.ConclusionThis study indicates that miRNA has-miR-542-5p is associated with TamR and can predict prognosis of breast cancer patients. Furthermore, has-miR-542-5p may be acting through a mechanism involving the target genes YWHAB, LY9, and SFRP1. Overall, has-miR-542-5p is a predictive biomarker and potential target for therapy of breast cancer patients.
Highlights
Tamoxifen is the first-line hormone therapy for estrogen receptor alpha positive (ERα+) breast cancer
This study indicates that miRNA has-miR-542-5p is associated with tamoxifen resistance (TamR) and can predict prognosis of breast cancer patients
Has-miR-542-5p may be acting through a mechanism involving the target genes Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Beta (YWHAB), Lymphocyte Antigen 9 (LY9), and Secreted Frizzled Related Protein 1 (SFRP1)
Summary
Tamoxifen is the first-line hormone therapy for estrogen receptor alpha positive (ERα+) breast cancer. About 40% of patients with ERα + breast cancer who receive tamoxifen therapy eventually develop resistance resulting in a poor prognosis. The aim of this study was to mine available data sets in the Gene Expression Omnibus (GEO) database, including in vitro (cell lines) and in vivo (tissue samples), and to identify all miRNAs associated with tamoxifen resistance (TamR) in breast cancer. This study aimed to predict the key gene regulatory networks of newly found TamR-related miRNAs and evaluate the potential role of the miRNAs and targets as potential prognosis biomarkers for breast cancer patients. Expressions of miR-190b and miR-516a-5p were altered in TamR cells and were predictive of treatment outcome in a cohort of ERα + breast cancer patients receiving adjuvant tamoxifen mono-therapy [13]; miR-519a confers TamR by targeting a network of tumor-suppressor genes in ERα + breast cancer [15]; miR-27b is epigenetically downregulated in TamR breast cancer cells due to promoter methylation and regulates tamoxifen sensitivity by targeting High Mobility Group Box 3 [16]; miR-320a sensitizes TamR breast cancer cells to tamoxifen by targeting CAMP Regulated Phosphoprotein 19 and ERRγ in breast cancer cells and tissues [17]; and miR-378a-3p regulates tamoxifen sensitivity in MCF-7 cells through targeting Golgi Transport 1A [18]
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