Prostaglandin E receptor 2 (EP2) regulates breast cancer stem-cell like property and promotes epithelial-mesenchymal transition

Abstract

BACKGROUND: Presence of cancer stem-like cells (CSCs) is the main obstacle for poor treatment response and mortality in breast cancer patients. Prostaglandin E receptors have been reported to play a role in epithelial-mesenchymal transition (EMT) and metastasis, however, the contribution on cancer stem cell compartment remains unstudied. METHODS: Human xenograft breast cancer model was used to study the expression of EP receptors during cancer development. Construction of stable EP2-expression cells was used to study tumorigenesis and characterization of EP2 receptor. Functional role of EP2 receptor on cell proliferation, flow cyometry, invasion and EMT gene expression array were performed in transfected cells. Expression of EP2 receptor was compared in primary tumor tissues by immunostaining and real-time PCR. RESULTS: EP2 receptor was predominantly expressed in animal tissues during cancer development, as well as in human primary tumor tissues. In mouse xenograft model, MB-231-EP2 clone developed a more aggressive tumor with a larger tumor size and showed a significant increase in cancer stem cell marker aldehyde hydrogenase (ALDH1) expression. In vitro study, MB-231-EP2 clone increased colony formation capacity and S-phase entry by the regulation of E-cadherin, TWIST1 and ALDH1. Importantly, we found that Twist1 expression level was higher in breast cancer patients than healthy controls and was associated with ALDH1 expression. CONCLUSIONS: These findings implicated that EP2 receptor was crucial to nurture CSC phenotype and promote tumorigenesis in breast cancer. Blocking of EP2 might be a potential therapeutic strategy to improve treatment response for breast cancer patients.