Loss of TBK1 Induces Epithelial–Mesenchymal Transition in the Breast Cancer Cells by ERα Downregulation

Kyung-Min Yang,Wonjoo Kim,Jin Ki Cho,Yunshin Jung,Jeong-Mi Lee,Joon Jeong,Seong-Jin Kim

doi:10.1158/0008-5472.can-13-0891

Kyung-Min Yang, Wonjoo Kim + Show 5 more

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https://doi.org/10.1158/0008-5472.can-13-0891

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Abstract

Estrogen receptor α (ERα) is the pivotal regulator of proliferation and differentiation in mammary epithelia, where it serves as a crucial prognostic marker and therapeutic target in breast cancer. In this study, we show that the loss of the kinase TANK-binding kinase 1 (TBK1) induces epithelial-mesenchymal transition in ERα-positive breast cancer cells by downregulating ERα expression. TBK1 was overexpressed in ERα-positive breast cancers, where it was associated with distant metastasis-free survival in patients, whereas it was underexpressed in ERα-negative breast cancers. TBK1 silencing decreased expression of epithelial markers and increased expression of mesenchymal markers in ERα-positive breast cancer cells, enhancing tumor growth and lung metastasis in vivo in a manner associated with downregulation of ERα expression. Mechanistically, TBK1 silencing reduced FOXO3A binding to the ERα promoter by inducing the translocation of phosphorylated FOXO3A from the nucleus to the cytoplasm. Thus, our results indicate that the loss of TBK1 expression parallels the loss of ERα expression, in turn helping drive an aggressive breast cancer phenotype.

Highlights

Breast cancer is one of the most common cancers among females, and 50% to 80% of breast tumors express estrogen receptor a (ERa; refs. 1, 2)
TANK-binding kinase 1 (TBK1) expression is associated with ERa expression status in breast cancers
These results suggest that the level of TBK1 expression is correlated with the level of ESR1 expression in breast cancer cells

Summary

Introduction

Breast cancer is one of the most common cancers among females, and 50% to 80% of breast tumors express estrogen receptor a (ERa; refs. 1, 2). Breast cancer is one of the most common cancers among females, and 50% to 80% of breast tumors express estrogen receptor a The major reason for this is that ERa-positive tumors initially respond well to anti-estrogen agents such as tamoxifen [5]. A significant proportion of ERa-positive tumors eventually become resistant to anti-estrogen therapy [6]. Breast cancer may be considered a broad set of diseases that includes multiple, distinct biological subtypes with diverse natural histories that present a varied spectrum of clinical, pathologic, and molecular features with different prognostic and therapeutic implications. ERa plays an important role in breast cancer development and progression by influencing the genes and signaling pathways that are involved in cellular proliferation.

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