Cytokines-activated nuclear IKKα-FAT10 pathway induces breast cancer tamoxifen-resistance

作     者：Xueyan Chen Weilin Wu Ji-Hak Jeong Matjaz Rokavec Rui Wei Shaolong Feng Werner Schroth Hiltrud Brauch Shangwei Zhong Jun-Li Luo 

作者机构：Department of OncologyXiangya HospitalCentral South UniversityChangsha 410008China Department of Molecular MedicineThe Scripps Research InstituteJupiter 33458USA Dr.Margarete Fischer-Bosch-Institute of Clinical PharmacologyStuttgart 70376Germany iFIT Cluster of ExcellenceUniversity of TübingenTübingen 72074Germany The Cancer Research Institute and the Second Affiliated HospitalHenyang Medical SchoolUniversity of South ChinaHengyang 421001China National Health Commission Key Laboratory of Birth Defect Research and PreventionHunan Provincial Maternal and Child Health Care HospitalChangsha 410008China 

出 版 物：《Science China(Life Sciences)》 (中国科学（生命科学英文版）)

年 卷 期：2024年第67卷第7期

页      面：1413-1426页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by a postdoctoral trainee fellowship from the Frenchman's Creek Women for Cancer Research,a cancer research fellowship from UICC(ACS-10-003) the Natural Science Foundation of China(81974469 and 81672635) the Postgraduate Independent Exploration and Innovation Project of Central South University of China(2019zzts899) 

主　　题：nuclear IKKα breast cancer Tam-resistance FAT10 Pax5 lymphotoxin nuclear IKKα-FAT0 pathway 

摘      要：Endocrine therapy that blocks estrogen signaling is the most effective treatment for patients with estrogen receptor positive(ER+)breast ***,the efficacy of agents such as tamoxifen(Tam)is often compromised by the development of *** we report that cytokines-activated nuclear IKKαconfers Tam resistance to ER+breast cancer by inducing the expression of FAT10,and that the expression of FAT10 and nuclear IKKαin primary ER+human breast cancer was correlated with lymphotoxinβ(LTB)expression and significantly associated with relapse and metastasis in patients treated with adjuvant ***αactivation or enforced FAT10 expression promotes Tam-resistance while loss of IKKαor FAT10 augments Tam *** induction of FAT10 by IKKαis mediated by the transcription factor Pax5,and coordinated via an IKKα-p53-miR-23a circuit in which activation of IKKαattenuates p53-directed repression of ***,our findings establish IKKα-to-FAT10 pathway as a new therapeutic target for the treatment of Tam-resistant ER+breast cancer.