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

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.