Abstract
ETS1 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 ETS1 in human breast cancer (BRCA) patients by investigating its expression patterns and methylation status in relation to clinical prognosis. ETS1 expression was significantly diminished by hyper-methylation of the ETS1 promoter region in specimens from BRCA patients compared to a healthy control group. Moreover, ETS1high BRCA patients showed better prognosis and longer survival compared to ETS1low BRCA patients. Consistent with clinical evidence, comparative transcriptome analysis combined with CRISPR/Cas9 or shRNA based perturbation of ETS1 expression revealed direct as well as indirect mechanisms of ETS1 that hinder tumorigenesis of BRCA cells. Taken together, our study enlightens a novel function of ETS1 as a tumor suppressor in breast cancer cells.
Highlights
Breast cancer is the most commonly diagnosed cancer and the second leading cause of death from cancer in women [1]
We found that BRCA patients in the ETS1low group were significantly more likely to have a poor prognosis in The Cancer Genome Atlas (TCGA) (P = 0.0165) as well as the Curtis (P = 0.0076) database (Figure 1C and Supplementary Figures 1A,B), compared to BRCA patients in ETS1high group not in triplenegative type specific manners (Supplementary Figures 1C,D) suggesting the potential of ETS1 as the anti-tumorigenic factor in breast cancer
Significantly reduced expression of ETS1 was observed in not all but specific types of cancers, including Bladder Urothelial Carcinoma (BLCA), colon adenocarcinoma (COAD), and Lung adenocarcinoma (LUAD), compared to normal specimens (Supplementary Figure 2A), which is highly correlated with poor clinical outcomes in general, consistent with BRCA (Supplementary Figure 2B)
Summary
Breast cancer is the most commonly diagnosed cancer and the second leading cause of death from cancer in women [1]. Development and progress of breast cancer are mediated by a complicated process in which many genes and signaling pathways are intertwined [2]. ETS1 Suppresses BRCA Tumorigenesis cells [6,7,8]. ETS1 is known to enhance the expression of numerous tumorigenic genes involved in tumor angiogenesis, cancer cell invasion, and energy metabolism [15]. These include vascular endothelial growth factor (VEGF) and certain proteases such as MMP-1, MMP-3, and MMP-9, as well as urokinase type plasminogen activator (uPA), which is associated with extracellular matrix (ECM) degradation [16,17,18,19]. The functionality and molecular action mechanisms of ETS1 in BRCA tumorigenesis still remain unclear
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