三阴性乳腺癌（TNBC）是治疗最具挑战性的乳腺癌亚型，由于其侵袭性特征和对现有临床治疗的低反应性而难以治疗。远处转移是TNBC患者死亡的主要原因。更好地理解TNBC转移机制可能会引领出新的早期诊断策略和更有效的治疗方法。在本研究中，我们揭示了自噬受体optineurin（OPTN）在TNBC转移中扮演了出人意料的角色。公开可获取的数据库数据挖掘揭示了TNBC患者OPTN mRNA水平与复发和远处转移无关的生存呈正相关。重要的是，体外和体内模型证实OPTN抑制TNBC转移。在机制上，OPTN通过与TGFβ type I 受体（TβRI）相互作用并促进其泛素化降解抑制了TNBC细胞的前癌变TGFβ信号。与我们的实验发现一致，临床TNBC样本显示OPTN mRNA表达水平与TGFβ基因响应特征和原型TGFβ靶基因表达呈负相关。总之，我们的研究证明OPTN是TGFβ受体/SMAD信号转导的负调节因子，抑制了TNBC的转移。本文受版权保护。保留所有权利。

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to its aggressive characteristics and low response to the existing clinical therapies. Distant metastasis is the main cause of death of TNBC patients. Better understanding of the mechanisms underlying TNBC metastasis may lead to new strategies of early diagnosis and more efficient treatment. In this study, we uncovered that the autophagy receptor optineurin (OPTN) plays an unexpected role in TNBC metastasis. Data mining of publicly available data bases revealed that the mRNA level of OPTN in TNBC patients positively correlates with relapse free and distance metastasis free survival. Importantly, in vitro and in vivo models demonstrated that OPTN suppresses TNBC metastasis. Mechanistically, OPTN inhibited the pro-oncogenic transforming growth factor-β (TGFβ) signaling in TNBC cells by interacting with TGFβ type I receptor (TβRI) and promoting its ubiquitination for degradation. Consistent with our experimental findings, the clinical TNBC samples displayed a negative correlation between OPTN mRNA expression and TGFβ gene response signature and expression of proto-typic TGFβ target genes. Altogether, our study demonstrates that OPTN is a negative regulator for TGFβ receptor/SMAD signaling and suppresses metastasis in TNBC. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.