Loss of ELF5-FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-γ signalling.,Nature Cell Biology

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Loss of ELF5-FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-γ signalling.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2020-04-13 , DOI: 10.1038/s41556-020-0495-y
Snahlata Singh ₁ , Sushil Kumar ₁ , Ratnesh Kumar Srivastava ₁ , Ajeya Nandi ₁ , Gatha Thacker ₁ , Hemma Murali ₁ , Sabrina Kim ₁ , Mary Baldeon ₁ , John Tobias ₂ , Mario Andres Blanco ₁ , Rizwan Saffie ₂ , M Raza Zaidi ₃ , Satrajit Sinha ₄ , Luca Busino ₂ , Serge Y Fuchs ₁ , Rumela Chakrabarti ₁

Affiliation

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.

中文翻译：

ELF5-FBXW7 的缺失可稳定 IFNGR1，从而通过干扰素-γ 信号传导促进三阴性乳腺癌的生长和转移。

三阴性乳腺癌（TNBC）的特点是肿瘤微环境中高度免疫浸润，这可能会影响TNBC细胞的命运。我们发现，TNBC 细胞中肿瘤抑制转录因子 Elf5 的缺失会激活内在的干扰素-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 Elf5 调节的泛素连接酶 FBXW7 的缺失确保了 TNBC 中其假定的蛋白质底物 IFN-γ 受体 1 (IFNGR1) 在蛋白质水平上的稳定。 Elf5low 肿瘤显示出 IFN-γ 信号增强，伴随着肿瘤微环境中免疫抑制性中性粒细胞的增加以及程序性死亡配体 1 表达的增加。程序性死亡配体 1 或 IFNGR1 的失活可引发强大的抗肿瘤和/或抗转移作用。 TNBC 患者肿瘤中 ELF5 和 FBXW7 表达之间的正相关性以及 ELF5、FBXW7 和 IFNGR1 表达之间的负相关性强烈表明，该信号轴可用于 Elf5low TNBC 患者的患者分层和免疫治疗策略。

更新日期：2020-04-24

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