Regulation of paired box 2 in breast cancer metastasis by EP2 receptor

Abstract

Background: Pro-tumorigenic actions of prostaglandin E receptors (EP1-EP4) have been shown in breast cancer and other solid tumors. Evidence suggest that EP2 receptor contributed to breast cancer progression and metastasis through different signaling pathways. This study aims to dissect the regulatory role of EP2 receptor in breast cancer metastasis. Methods: A stable EP2-overexpressing cells were developed to study the tumor growth and metastasis in human xenograft breast cancer model. Correlation analysis and survival analysis were used to evaluate the relationship between EP2 and PAX2, and the correlation with clinical outcome of the patients respectively. In-silico prediction tool and luciferase reporting assay were used to identify the putative target of EP2. Result: Higher expression of EP2 was seen in triple-negative breast cancer than other subtypes, and were associated with poor prognosis. Silencing of EP2 reduced tumorsphere generating ability and ABCG2 expression. In human xenograft breast cancer model, EP2-overexpressing cells promoted the growth of xenograft tumors and had more metastatic nodules. Various EMT-related gene expressions were altered in metastatic tumors of the xenografts. Moreover, PAX2 has been identified as the putative downstream target of EP2 by luciferase reporting assay. PAX2 expression significantly upregulated in tumor tissues and had a positive correlation between EP2 and PAX2 expression in paired primary tissues. Importantly, knockdown of PAX2 by RNA interference reduced cell proliferation and migration. Conclusions: This study revealed a novel EP2-driven signaling cascade to promote cancer growth and metastasis through regulation of PAX2. Targeting EP2/PAX2 axis may offer a new treatment options for advanced breast cancer.