Abstract
Eyes absent homolog 2 (EYA2), a transcriptional activator, is pivotal for organ development, but aberrant regulation of EYA2 has been reported in multiple human tumors. However, the role of EYA2 in breast cancer is still lack of full understanding. To explore the biological significance of EYA2 in breast cancer, we conducted data analysis on public breast cancer datasets, and performed immunohistochemistry (IHC) analysis, colony-forming unit assays, EdU assay, western blotting, and immunofluorescence (IF). Meta-analysis showed that EYA2 mRNA expression was correlated with tumor grade, the status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). IHC analysis displayed that EYA2 protein abundance was inversely associated with the status of ER and PR, and enriched in triple-negative breast cancer in comparison with luminal-type tumors. Additionally, correlation analysis reflected that EYA2 mRNA was negatively correlated with luminal markers, and positively associated with markers of basal cells, epithelial-mesenchymal transition and cancer stem cells. Clone-forming assay and EdU experiment showed that EYA2 overexpression enhanced proliferation of breast cancer cells. Results from western blotting and IF displayed that overexpression of EYA2 up-regulated the protein abundance of proliferation markers. Importantly, survival analysis indicated that higher EYA2 mRNA level predicted worse overall survival, relapse-free survival and metastasis-free survival among whole enrolled breast cancer patients. Collectively, EYA2 was closely correlated with clinico-pathological characteristics, and served as a proliferation stimulator for breast cancer cells and an unfavorable prognostic element for breast cancer patients, suggesting that EYA2 is involved in the progression of breast carcinoma.
Highlights
Breast cancer is the leading cancer type in women and poses a major threat to public health worldwide [1]
The results showed that Eyes absent homolog 2 (EYA2) mRNA expression was remarkably lower in cancerous tissues than in non-cancerous tissues [Odds ratio (OR): 0.21 (0.10–0.43), I2 = 0.0%; Figure 1A]
The results indicated that protein abundance of EYA2 was significantly higher in estrogen receptor (ER)– (p = 0.005) (Figure 2B) or progesterone receptor (PR)– (p = 0.004) (Figure 2C) in comparison with ER+ or PR+ cancer tissues, respectively
Summary
Breast cancer is the leading cancer type in women and poses a major threat to public health worldwide [1]. EYA2 promoted cell cycle progression of tumor cells via the up-regulation of cyclin D1 and cyclin E [17]. Knockdown of EYA2 by siRNA reduced the proliferation through cell cycle G1 block and enhanced the apoptosis of lung adenocarcinoma cells [20]. One previous research demonstrated that EYA2 overexpression was an unfavorable molecule for tumor growth of pancreatic adenocarcinoma in orthotopic models [21]. EYA2 can contribute to tumor invasion and metastasis for some cancer types, including breast cancer [18], lung adenocarcinoma [22], and astrocytoma [17]. Several mechanisms might underlie the role of EYA2 in tumor invasion, including the activation of ERK signaling [17] and the promotion of epithelial-mesenchymal transition (EMT) [18]. High EYA2 level has been demonstrated to be a negative element for prognosis in lung cancer [16], while EYA2 predicted better clinical outcomes in colorectal cancer [15] and pancreatic cancer [21]
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