Elevated expression of TANK-binding kinase 1 enhances tamoxifen resistance in breast cancer

Abstract

Resistance to antiestrogens is one of the major challenges in breast cancer treatment. Although phosphorylation of estrogen receptor α (ERα) is an important factor in endocrine resistance, the contributions of specific kinases in endocrine resistance are still not fully understood. Here, we report that an important innate immune response kinase, the IκB kinase-related TANK-binding kinase 1 (TBK1), is a crucial determinant of resistance to tamoxifen therapies. We show that TBK1 increases ERα transcriptional activity through phosphorylation modification of ERα at the Ser-305 site. Ectopic TBK1 expression impairs the responsiveness of breast cancer cells to tamoxifen. By studying the specimens from patients with breast cancer, we find a strong positive correlation of TBK1 with ERα, ERα Ser-305, and cyclin D1. Notably, patients with tumors highly expressing TBK1 respond poorly to tamoxifen treatment and show high potential for relapse. Therefore, our findings suggest that TBK1 contributes to tamoxifen resistance in breast cancer via phosphorylation modification of ERα.T ANK-binding kinase 1 (TBK1) and IκB kinase e (IKKe) are two IKK-related serine/threonine kinases that display 64% sequence identity and trigger the antiviral response of interferons (IFN) through NF-κB activation and interferon regulatory transcription factor (IRF) 3/7 phosphorylation (1-3). In addition to the proposed roles of IKK-related kinases in controlling transcription factors NF-κB and IRF, the involvement of TBK1 and IKKe in AKT-induced oncogenic transformation has been demonstrated in a recent study (4). TBK1 is identified as a Raslike (Ral) B effector in the Ral guanine nucleotide exchange factor pathway that is required for Ras-induced transformation (5). IKKe acts downstream of the PI3K-AKT pathway and cooperates with activated MEK to promote cellular transformation (6). IKKe has also been identified recently as a breast cancer oncogene that is frequently amplified or overexpressed in human breast cancer, and the phosphorylation of ERα by IKKe contributes to tamoxifen resistance in breast cancer (7-9). Interestingly, TBK1 is also highly expressed in breast cancer (10), and knocking down TBK1 diminishes the viability of MCF-7 cells (9). However, the exact role of TBK1 in breast cancer remains unclear.Estrogen receptor α (ERα) is a nuclear receptor that exerts a profound influence on the initiation and progression of breast cancer by regulating cell transformation, proliferation, and metastasis (11-13). For ERα-positive patients with breast cancer, targeting the ER signaling pathway with tamoxifen, a selective ER modulator, is efficacious in both prevention and treatment of breast cancer (14). Unfortunately, a substantial proportion of patients are intrinsically resistant to this therapy, and a significant number of patients with advanced disease eventually develop acquired resistance to the treatment (15-18). ERα is a key determinant of breast cancer susceptibility to endocrine therapy. Recent studies demonstrate that ERα phosphorylation ...

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Identification and Further Development of Potent TBK1 Inhibitors

“…9,12,24 Since TBK1 may represent a future drug target in cancer therapy, the identification and development of novel inhibitors to modulate TBK1 kinase activity is an important area of research. Currently known inhibitors such as BX795 10,11 or CYT387 25 ( Figure 1) were potent TBK1 inhibitors but lacked specificity, which rendered them unfeasible for application as molecular probes to decipher TBK1 biology.…”

Pharmacological inhibition of the IKKε/TBK-1 axis potentiates the anti-tumour and anti-metastatic effects of Docetaxel in mouse models of breast cancer

“…Previous studies have implicated members of the NF B pathway in increased resistance to various chemotherapies [9,[35][36][37]. Of all the chemotherapeutic agents tested (Docetaxel, Cyclophosphamide, Doxorubicin, Rapamycin, 5-Fluorouracil and Tamoxifen; data not shown), only Docetaxel significantly enhanced IKK expression in parental MDA-MB-231 breast cancer cells ( Fig.…”