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.
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Acknowledgement
This work was supported by a postdoctoral trainee fellowship from the Frenchman’s Creek Women for Cancer Research, a cancer research fellowship from UICC (ACS-10-003), and the Natural Science Foundation of China (81974469 and 81672635), the Postgraduate Independent Exploration and Innovation Project of Central South University of China (2019zzts899). We thank Wenyi Wei (Harvard Medical School) for kindly providing the MDM2 expression plasmid, Michael Karin (UCSD) for kindly providing IKKα plasmids and knockout mice.
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Chen, X., Wu, W., Jeong, JH. et al. Cytokines-activated nuclear IKKα-FAT10 pathway induces breast cancer tamoxifen-resistance. Sci. China Life Sci. 67, 1413–1426 (2024). https://doi.org/10.1007/s11427-023-2460-0
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DOI: https://doi.org/10.1007/s11427-023-2460-0