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...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 IKKαconfers Tam resistance to ER+breast cancer by inducing the expression of FAT10,and that the expression of FAT10 and nuclear IKKαin primary ER+human breast cancer was correlated with lymphotoxinβ(LTB)expression and significantly associated with relapse and metastasis in patients treated with adjuvant mono-Tam.IKKαactivation or enforced FAT10 expression promotes Tam-resistance while loss of IKKαor FAT10 augments Tam sensitivity.The induction of FAT10 by IKKαis mediated by the transcription factor Pax5,and coordinated via an IKKα-p53-miR-23a circuit in which activation of IKKαattenuates 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.展开更多
基金supported by a postdoctoral trainee fellowship from the Frenchman's Creek Women for Cancer Research,a cancer research fellowship from UICC(ACS-10-003)the Natural Science Foundation of China(81974469 and 81672635)the Postgraduate Independent Exploration and Innovation Project of Central South University of China(2019zzts899)。
文摘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 IKKαconfers Tam resistance to ER+breast cancer by inducing the expression of FAT10,and that the expression of FAT10 and nuclear IKKαin primary ER+human breast cancer was correlated with lymphotoxinβ(LTB)expression and significantly associated with relapse and metastasis in patients treated with adjuvant mono-Tam.IKKαactivation or enforced FAT10 expression promotes Tam-resistance while loss of IKKαor FAT10 augments Tam sensitivity.The induction of FAT10 by IKKαis mediated by the transcription factor Pax5,and coordinated via an IKKα-p53-miR-23a circuit in which activation of IKKαattenuates 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.
