Loss of ELF5-FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-γ signalling.
Loss of ELF5-FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-γ signalling.
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DOI：
10.1038/s41556-020-0495-y
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发表时间：
2020-05
影响因子：
21.3
通讯作者：
Chakrabarti R
中科院分区：
文献类型：
--
作者：
Singh S;Kumar S;Srivastava RK;Nandi A;Thacker G;Murali H;Kim S;Baldeon M;Tobias J;Blanco MA;Saffie R;Zaidi MR;Sinha S;Busino L;Fuchs SY;Chakrabarti R
三阴性乳腺癌（TNBC）的特征在于肿瘤微环境中的高度免疫浸润，这可能影响TNBC细胞的命运。我们揭示了TNBC细胞中肿瘤抑制性转录因子Elf 5的缺失激活了内在干扰素-γ（IFN-γ）信号传导，促进肿瘤进展和转移。从机制上讲，我们发现Elf 5调节的泛素连接酶FBXW 7的丧失确保了其推定的蛋白底物IFN-γ受体1（IFNGR 1）在TNBC中蛋白水平的稳定。Elf 5low肿瘤显示增强的IFN-γ信号传导，伴随着肿瘤微环境中免疫抑制性中性粒细胞的增加和程序性死亡配体1表达的增加。程序性死亡配体1或IFNGR 1的失活引起了强有力的抗肿瘤和/或抗转移作用。在患有TNBC的患者的肿瘤中，ELF 5和FBXW 7表达之间的正相关性以及ELF 5、FBXW 7和IFNGR 1表达之间的负相关性强烈地表明，该信号传导轴可以用于患有TNBC的Elf 5低患者的患者分层和免疫治疗策略。
Triple-negative breast cancer (TNBC) is characterized by a high degree of immune infiltrate in the tumour microenvironment, which may influence the fate of TNBC cells. We reveal that loss of the tumour suppressive transcription factor Elf5 in TNBC cells activates intrinsic interferon-γ (IFN-γ) signalling, promoting tumour progression and metastasis. Mechanistically, we find that loss of the Elf5-regulated ubiquitin ligase FBXW7 ensures stabilization of its putative protein substrate IFN-γ receptor 1 (IFNGR1) at the protein level in TNBC. Elf5low tumours show enhanced IFN-γ signalling accompanied by an increase of immunosuppressive neutrophils within the tumour microenvironment and increased programmed death ligand 1 expression. Inactivation of either programmed death ligand 1 or IFNGR1 elicited a robust anti-tumour and/or anti-metastatic effect. A positive correlation between ELF5 and FBXW7 expression and a negative correlation between ELF5, FBXW7 and IFNGR1 expression in the tumours of patients with TNBC strongly suggest that this signalling axis could be exploited for patient stratification and immunotherapeutic treatment strategies for Elf5low patients with TNBC.
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