Abstract

Breast cancer metastasis accounts for most of the deaths from breast cancer. Since epithelial-mesenchymal transition (EMT) plays an important role in promoting metastasis of cancer, many mechanisms regarding EMT have been studied. We previously showed that Ribonucleic acid export 1 (RAE1) is dysregulated in breast cancer and its overexpression leads to aggressive breast cancer phenotypes by inducing EMT. Here, we evaluated the functional capacity of RAE1 in breast cancer metastasis by using a three-dimensional (3D) culture system and xenograft models. Furthermore, to investigate the mechanisms of RAE1-driven EMT, in vitro studies were carried out. The induction of EMT with RAE1-overexpression was confirmed under the 3D culture system and in vivo system. Importantly, RAE1 mediates upregulation of an EMT marker ZEB1, by binding to the promoter region of ZEB1. Knockdown of ZEB1 in RAE1-overexpressing cells suppressed invasive and migratory behaviors, accompanied by an increase in epithelial and a decrease in mesenchymal markers. Taken together, these data demonstrate that RAE1 contributes to breast cancer metastasis by regulating a key EMT-inducing factor ZEB1 expression, suggesting its potential as a therapeutic target.

Highlights

  • Breast cancer is one of the most commonly occurring cancers in women worldwide[1]

  • With the expectation that Ribonucleic acid export 1 (RAE1) would be a useful target for cancer therapy, we carried out functional studies in breast cancer cell lines and found that RAE1 contributes to aggressive cancer cell phenotype and induces EMT18

  • RAE1 overexpression enhances cell spreading in 3D culture systems and metastasis in mouse xenograft models

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Summary

Introduction

Breast cancer is one of the most commonly occurring cancers in women worldwide[1]. The main reason for death of breast cancer patients is metastasis[2]. EMT has been highlighted in breast cancer resistance to chemotherapy and/or target therapies[8,9,10,11]. With the expectation that RAE1 would be a useful target for cancer therapy, we carried out functional studies in breast cancer cell lines and found that RAE1 contributes to aggressive cancer cell phenotype and induces EMT18. The expression level of RAE1 was positively correlated with the histologic grading in breast cancer patients with invasive ductal carcinoma[18]. We investigated how RAE1 contributes to invasion and metastasis of breast cancer, three-dimensional (3D) culture system and xenograft models. Our in vitro studies have revealed that RAE1 induces EMT by enhancing the expression of transcription factor ZEB1. Www.nature.com/scientificreports the metastatic potential of breast cancer, our results support the relationship between RAE1 activity and breast cancer aggressiveness

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