Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, 33458, USA.
Sci China Life Sci. 2024 Jul;67(7):1413-1426. doi: 10.1007/s11427-023-2460-0. Epub 2024 Apr 1.
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.
阻断雌激素信号的内分泌治疗是治疗雌激素受体阳性（ER）乳腺癌患者最有效的方法。然而，他莫昔芬（Tam）等药物的疗效常常因耐药性的发展而受到影响。在这里，我们报告细胞因子激活的核 IKKα 通过诱导 FAT10 的表达赋予 ER 乳腺癌对 Tam 的耐药性，并且在原发性 ER 人乳腺癌中，FAT10 和核 IKKα 的表达与淋巴毒素β（LTB）的表达相关，并与接受辅助单 Tam 治疗的患者的复发和转移显著相关。IKKα 的激活或强制表达 FAT10 可促进 Tam 耐药性，而 IKKα 或 FAT10 的缺失则增强 Tam 的敏感性。IKKα 通过转录因子 Pax5 介导 FAT10 的诱导，通过 IKKα-p53-miR-23a 通路进行协调，其中 IKKα 的激活减弱了 p53 对 FAT10 的抑制作用。因此，我们的研究结果确立了 IKKα-to-FAT10 途径作为治疗 Tam 耐药性 ER 乳腺癌的新治疗靶点。
