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

Estrogen receptor alpha (ER alpha) 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 ER alpha-positive breast cancer cells by downregulating ER alpha expression. TBK1 was overexpressed in ERa-positive breast cancers, where it was associated with distant metastasis-free survival in patients, whereas it was underexpressed in ER alpha-negative breast cancers. TBK1 silencing decreased expression of epithelial markers and increased expression of mesenchymal markers in ER alpha-positive breast cancer cells, enhancing tumor growth and lung metastasis in vivo in a manner associated with downregulation of ER alpha expression. Mechanistically, TBK1 silencing reduced FOXO3A binding to the ER alpha 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 ER alpha expression, in turn helping drive an aggressive breast cancer phenotype. (C) 2013 AACR.