DNER promotes epithelial\u2013mesenchymal transition and prevents chemosensitivity through the Wnt/\u03b2-catenin pathway in breast cancer

Zhong Wang,Changhua Wang,Chenyuan Li,Yimin Zhang,Juanjuan Li,Zhiyu Li,Shengrong Sun,Qi Wu,Si Sun

doi:10.1038/s41419-020-02903-1

Zhong Wang, Changhua Wang + Show 7 more

Open Access

https://doi.org/10.1038/s41419-020-02903-1

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Abstract

Breast cancer (BC) is the most common malignant tumour in women worldwide, and one of the most common fatal tumours in women. Delta/Notch-like epidermal growth factor (EGF)-related receptor (DNER) is a transmembrane protein involved in the development of tumours. The role and potential mechanism of DNER in epithelial–mesenchymal transition (EMT) and apoptosis in BC are not fully understood. We find that DNER is overexpressed in BC tissue, especially triple-negative breast cancer (TNBC) tissue, and related to the survival of BC and TNBC patients. In addition, DNER regulates cell EMT to enhance the proliferation and metastasis of BC cells via the Wnt/β-catenin pathway in vitro and in vivo. Moreover, the expression levels of β-catenin and DNER in BD tissue are positively correlated. The simultaneously high expression of DNER and β-catenin contributes to poor prognosis in BC patients. Finally, DNER protects BC cells from epirubicin-induced growth inhibition and apoptosis via the Wnt/β-catenin pathway. In conclusion, these results suggest that DNER induces EMT and prevents apoptosis by the Wnt/β-catenin pathway, ultimately promoting the malignant progression of BC. In conclusion, our study demonstrates that DNER functions as an oncogene and potentially valuable therapeutic target for BC.

Highlights

Breast cancer (BC) is the most common malignant tumour in women worldwide and one of the most common fatal tumours in women[1,2]
DNER is upregulated in BC tissues and correlated with poor prognosis in BC and triple-negative breast cancer (TNBC) patients
To verify whether the poor prognosis of BC patients caused by DNER is related to epithelial–mesenchymal transition (EMT), we detected the correlation between DNER- and EMT-related markers

Summary

Introduction

Breast cancer (BC) is the most common malignant tumour in women worldwide and one of the most common fatal tumours in women[1,2]. Tumour recurrence and metastasis and chemotherapeutic resistance are the most common causes of cancer treatment failure. The need to screen and identify key regulatory factors in the process of tumour recurrence and metastasis for the treatment of BC is urgent. EMT, a crucial regulatory mechanism by which tumours acquire invasive and metastatic abilities and the ability to resist apoptosis, plays an irreplaceable role in the development of malignant tumours[8,9,10]. Recent studies upon activation of the classical Wnt/β-catenin pathway, β-catenin enters and accumulates in the nucleus, which induces the transcription and translation of downstream target genes, accelerating EMT10. Maintaining β-catenin activity is important for the Wnt/β-catenin pathway and tumour progression. DNER is expressed at abnormally high levels in Official journal of the Cell Death Differentiation Association

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