ETS1 Suppresses Tumorigenesis of Human Breast Cancer via Trans-Activation of Canonical Tumor Suppressor Genes

Abstract

<i>ETS1</i> has shown dichotomous roles as an oncogene and a tumor suppressor gene in diverse cancers, but its functionality in breast cancer tumorigenesis still remains unclear. We utilized the Cancer Genome Atlas (TCGA) database to analyze comprehensive functions of <i>ETS1</i> in human breast cancer (BRCA) patients by investigating its expression patterns and methylation status in relation to clinical prognosis. <i>ETS1</i> expression was significantly diminished by hyper-methylation of the <i>ETS1</i> promoter region in specimens from BRCA patients compared to a healthy control group. Moreover, <i>ETS1</i> ^high BRCA patients showed better prognosis and longer survival compared to <i>ETS1</i> ^low BRCA patients. Consistent with clinical evidence, comparative transcriptome analysis combined with CRISPR/Cas9 or shRNA based perturbation of <i>ETS1</i> expression revealed direct as well as indirect mechanisms of <i>ETS1</i> that hinder tumorigenesis of BRCA cells. Taken together, our study enlightens a novel function of <i>ETS1</i> as a tumor suppressor in breast cancer cells.