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

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

doi:10.1007/s11427-023-2460-0

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

Sci China Life Sci. 2024 Apr 1. doi: 10.1007/s11427-023-2460-0. Online ahead of print.

Authors

Xueyan Chen^#^{1

2}, Weilin Wu^#², Ji-Hak Jeong², Matjaz Rokavec², Rui Wei¹, Shaolong Feng², Werner Schroth^{3

4}, Hiltrud Brauch^{3

4}, Shangwei Zhong^{5

6}, Jun-Li Luo^{7

8

9

10}

Affiliations

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 Department of Molecular Medicine, The Scripps Research Institute, Jupiter, 33458, USA. swzhong@usc.edu.cn.
⁶ The Cancer Research Institute and the Second Affiliated Hospital, Henyang Medical School, University of South China, Hengyang, 421001, China. swzhong@usc.edu.cn.
⁷ Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China. jlluo@usc.edu.cn.
⁸ Department of Molecular Medicine, The Scripps Research Institute, Jupiter, 33458, USA. jlluo@usc.edu.cn.
⁹ The Cancer Research Institute and the Second Affiliated Hospital, Henyang Medical School, University of South China, Hengyang, 421001, China. jlluo@usc.edu.cn.
¹⁰ National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, 410008, China. jlluo@usc.edu.cn.

^# Contributed equally.

PMID: 38565741
DOI: 10.1007/s11427-023-2460-0

Abstract

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 promotes Tam-resistance while loss of IKKα or FAT10 augments Tam sensitivity. The induction of FAT10 by IKKα is mediated by the transcription factor Pax5, and coordinated via an IKKα-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.

Keywords: FAT10; Pax5; Tam-resistance; breast cancer; lymphotoxin; nuclear IKKα; nuclear IKKα-FAT0 pathway.