Elevated expression of TANK-binding kinase 1 enhances tamoxifen resistance in breast cancer.
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.
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, China.
Congwen
C
Wei
Yuan
Y
Cao
Xiaoli
X
Yang
Zirui
Z
Zheng
Kai
K
Guan
Qiang
Q
Wang
Yanhong
Y
Tai
Yanhong
Y
Zhang
Shengli
S
Ma
Ye
Y
Cao
Xiaoxing
X
Ge
Changzhi
C
Xu
Jia
J
Li
Hui
H
Yan
Youguo
Y
Ling
Ting
T
Song
Lin
L
Zhu
Buchang
B
Zhang
Quanbin
Q
Xu
Chengjin
C
Hu
Xiu-wu
XW
Bian
Xiang
X
He
Hui
H
Zhong
D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D053208:Kaplan-Meier Estimate; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects; D016896:Treatment Outcome
C530104:CCND1 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; D019938:Cyclin D1; D010768:Phosphoserine; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human