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 

机构地区：[1]Department of Oncology,Xiangya Hospital,Central South University,Changsha 410008,China [2]Department of Molecular Medicine,The Scripps Research Institute,Jupiter 33458,USA [3]Dr.Margarete Fischer-Bosch-Institute of Clinical Pharmacology,Stuttgart 70376,Germany [4]iFIT Cluster of Excellence,University of Tübingen,Tübingen 72074,Germany [5]The Cancer Research Institute and the Second Affiliated Hospital,Henyang Medical School,University of South China,Hengyang 421001,China [6]National Health Commission Key Laboratory of Birth Defect Research and Prevention,Hunan Provincial Maternal and Child Health Care Hospital,Changsha 410008,China

出　　处：《Science China(Life Sciences)》2024年第7期1413-1426,共14页中国科学（生命科学英文版）

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)。

摘　　要：Endocrine therapy that blocks estrogen signaling is the most effective treatment for patients with estrogen receptor positive(ER+)breast cancer.However,the efficacy of agents such as tamoxifen(Tam)is often compromised by the development of resistance.Here 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 mono-Tam.IKKαactivation or enforced FAT10 expression promotes Tam-resistance while loss of IKKαor FAT10 augments Tam sensitivity.The 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 FAT10.Thus,our findings establish IKKα-to-FAT10 pathway as a new therapeutic target for the treatment of Tam-resistant ER+breast cancer.

关 键 词：nuclear IKKα breast cancer Tam-resistance FAT10 Pax5 lymphotoxin nuclear IKKα-FAT0 pathway 

分 类 号：R737.9[医药卫生—肿瘤]