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

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外文摘要：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 IKKα confers Tam resistance to ER+breast cancer by inducing the expression of FAT10,and that the expression of FAT10 and nuclear IKKα in primary ER+human breast cancer was correlated with lymphotoxin β(LTB)expression and significantly associated with relapse and metastasis in patients treated with adjuvant mono-Tam.IKKα activation or enforced FAT10 expression pro-motes Tam-resistance while loss of IKKα or FAT10 augments Tam sensitivity.The induction of FAT10 by IKKα is mediated by the tran-scription factor Pax5,and coordinated via an KKα-p53-miR-23a circuit in which activation of IKKα attenuates 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.

外文关键词：

nuclear IKKαbreast cancerTam-resistanceFAT10Pax5lymphotoxinnuclear IKKα-FATO pathway

作者：

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

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作者单位：

Department of Oncology,Xiangya Hospital,Central South University,Changsha 410008,China

Department of Molecular Medicine,The Scripps Research Institute,Jupiter 33458,USA

Dr.Margarete Fischer-Bosch-Institute of Clinical Pharmacology,Stuttgart 70376,Germany

iFIT Cluster of Excellence,University of Tübingen,Tübingen 72074,Germany

The Cancer Research Institute and the Second Affiliated Hospital,Henyang Medical School,University of South China,Hengyang 421001,China

National Health Commission Key Laboratory of Birth Defect Research and Prevention,Hunan Provincial Maternal and Child Health Care Hospital,Changsha 410008,China

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基金：

Frenchman's Creek Women for Cancer Research,a cancer research fellowship from UICCNatural Science Foundation of ChinaNatural Science Foundation of ChinaPostgraduate Independent Exploration and Innovation Project of Central South University of China

项目编号：

ACS-10-00381974469816726352019zzts899

出版年：

2024

DOI：

10.1007/s11427-023-2460-0

中国科学:生命科学(英文版)

中国科学院

中国科学:生命科学(英文版)

CSTPCD

影响因子：0.806

ISSN：1674-7305

年,卷(期)：2024.67(7)