Overexpression of miR-489 enhances efficacy of 5-fluorouracil-based treatment in breast cancer stem cells by targeting XIAP.

Xuedong Wang,Ming Zhou,Soldano Ferrone,Xinhui Wang,Juan Gu,Zhimin He,Xinguo Wang

doi:10.18632/oncotarget.22985

Abstract

Population of cancer stem cells (CSCs) in breast cancer is reported to be resistant to chemotherapy. Furthermore, many cases of treatment failure are induced by the chemoresistance of CSCs in breast cancer patients. Therefore, novel strategies should be explored urgently to reverse drug-resistance in breast cancer stem cells (BCSCs). In this study, we isolated and cultured the BCSCs from the T-47D and SKBR3 breast cancer cell lines. We observed significant resistance to 5-fluorouracil in BCSCs. Mechanically, we found that expression of miR-489 was decreased in BCSCs. Furthermore, overexpression of miR-489 was found to increase the cytotoxicity of 5-fluorouracil to BCSCs. XIAP, a key anti-apoptotic protein, was proved to be the target of miR-489. We found that enforced expression of XIAP through its recombinant expression vector abolished the effect of miR-489 on reversing the 5-fluorouracil resistance. On the contrary, embelin, a XIAP specific inhibitor, was found to sensitize BCSCs to 5-fluorouracil similarly with miR-489. In summary, our data demonstrate that introduction with miR-489 represents a novel strategy to enhance efficacy of 5-fluorouracil-based treatment in BCSCs.

Highlights

Breast cancer represents a common malignant tumor, which usually leads to a high mortality rate in women worldwide [1]
We found that enforced expression of X-linked Inhibitor of Apoptosis Protein (XIAP) through its recombinant expression vector abolished the effect of miR-489 on reversing the 5-fluorouracil resistance
After separating and culturing these breast cancer stem cells (BCSCs), we performed MTT assays to investigate the resistance of T-47D and SKBR3 cancer stem cells (CSCs) to 5-FU treatment

Summary

Introduction

Breast cancer represents a common malignant tumor, which usually leads to a high mortality rate in women worldwide [1]. CD44+/CD24-/low phenotype of breast cancer cells are reported to exhibit highly tumorigenic and self-renewing capability. This population of tumor cells are called breast cancer stem cells (BCSCs) [2, 3]. BCSCs are found to be resistant to chemotherapy. Many cases of treatment failure are induced by the chemoresistance of CSCs in breast cancer patients [4, 5, 6, 7]. It’s urgent to develop CSC-targeting therapies to enhances efficacy of chemotherapy in breast cancer

Methods

Results

Conclusion