MicroRNA-155, induced by FOXP3 through transcriptional repression of BRCA1, is associated with tumor initiation in human breast cancer.

Song Gao,Ranji Cui,Kai Jiao,Ling Ouyang,Zhengwei Yuan,Zhiying Zhao,Rong Wu,Yicun Wang,Runhua Liu,Lizhong Wang,Meng Wang,Zhi Li,Raymond X Wang

doi:10.18632/oncotarget.17816

Abstract

MicroRNA (miR)-155 is upregulated in breast cancer cells and in sera of patients with breast cancer, but its clinical relevance remains uncertain. The objective of the present effort was to address the transcriptional regulation of miR-155. A bioinformatics analysis of public datasets validated upregulation of miR-155 in tumor cells of patients with breast cancer, particularly those who were at early stages and had triple-negative cancers. The expression profiling and clinical relevance of miR-155 in tumor cells and blood cells were characterized by TaqMan miR assays and, in plasma and exosomes, by nest-quantitative PCR analysis. There was a positive correlation between expression of FOXP3 and miR-155 in breast cancer cell lines and primary breast cancers. In breast cancer cells, FOXP3 induced miR-155 through transcriptional repression of BRCA1. Furthermore, in an Alabama cohort, blood and plasma samples were collected from 259 participants, including patients with breast cancer or benign breast tumors, members of breast cancer families, and matched healthy female controls. For patients with early stage or localized breast cancer, there were high levels of miR-155 in both plasma and blood cells. In cultured breast cancer cells, expression of miR-155 was induced by FOXP3 but was not significantly changed in culture medium or exosomes, suggesting that circulating miR-155 originated from blood cells. These findings reveal a transcriptional axis of FOXP3-BRCA1-miR-155 in breast cancer cells and show that plasma miR-155 may serve as a non-invasive biomarker for detection of early stage breast cancer.

Highlights

MicroRNAs are small, noncoding RNAs that control expression of target genes through inhibiting protein translation or inducing degradation of mRNA transcripts of target genes [1]
These findings reveal a transcriptional axis of FOXP3-BRCA1-miR-155 in breast cancer cells and show that plasma miR-155 may serve as a non-invasive biomarker for detection of early stage breast cancer
To assess the clinical relevance of miR-155 in human primary breast cancers, the expression profile of miR-155 was characterized by bioinformatics analysis of public datasets from a) the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) and b) the National Cancer Institute (NCI) The Cancer Genome Atlas (TCGA)

Summary

Introduction

MicroRNAs (miRs) are small, noncoding RNAs that control expression of target genes through inhibiting protein translation or inducing degradation of mRNA transcripts of target genes [1]. It has functions in proliferation, apoptosis, angiogenesis, and the epithelial–mesenchymal transition (EMT). Ectopic overexpression of miR-155 enhances proliferation in human breast cancer cells and tumor growth in breast cancer xenografts, while antisense targeting of miR155 inhibits proliferation, angiogenesis, migration, and invasion, as well as the EMT, but induces cell cycle arrest, apoptosis, and enhances their response to radiation and chemotherapy [5,6,7,8,9,10]. There are two negative transcriptional regulators of miR155, BRCA1 [7] and p63 [21]. Needed is identification of positive transcriptional regulators of miR-155 for identifying new therapeutic targets in human breast cancer

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Results

Conclusion