TMEM25 inhibits monomeric EGFR-mediated STAT3 activation in basal state to suppress triple-negative breast cancer progression.
TMEM25 inhibits monomeric EGFR-mediated STAT3 activation in basal state to suppress triple-negative breast cancer progression.
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DOI：
10.1038/s41467-023-38115-2
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发表时间：
2023-04-24
影响因子：
16.6
通讯作者：
Wang, Hong-Rui
中科院分区：
文献类型：
--
作者：
Bi, Jing;Wu, Zhihui;Zhang, Xin;Zeng, Taoling;Dai, Wanjun;Qiu, Ningyuan;Xu, Mingfeng;Qiao, Yikai;Ke, Lang;Zhao, Jiayi;Cao, Xinyu;Lin, Qi;Chen, Xiao Lei;Xie, Liping;Ouyang, Zhong;Guo, Jujiang;Zheng, Liangkai;Ma, Chao;Guo, Shiying;Chen, Kangmei;Mo, Wei;Fu, Guo;Zhao, Tong-Jin;Wang, Hong-Rui
三阴性乳腺癌(TNBC)是乳腺癌的一种亚型，预后差，缺乏公认的靶向治疗。表皮生长因子受体(EGFR)的过度表达在50%以上的TNBC中被发现，并被认为是TNBC进展的动力；然而，使用抗体靶向EGFR以防止其二聚化和激活对TNBC患者没有明显的好处。在此，我们报道了在缺少跨膜蛋白TMEM25的情况下，EGFR单体可以激活信号转导转录激活因子3(STAT3)，而TMEM25在人TNBC中的表达经常降低。缺乏TMEM25允许EGFR单体独立于配体结合而磷酸化STAT3，从而增强STAT3的基础激活以促进雌性小鼠TNBC的进展。此外，用腺相关病毒提供TMEM25可以强烈抑制STAT3的激活和TNBC的进展。因此，我们的研究揭示了单体-EGFR/STAT3信号通路在TNBC进展中的作用，并指出了一种潜在的针对TNBC的靶向治疗。EGFR异常表达与三阴性乳腺癌(TNBC)相关。在这里，作者发现TMEM25与EGFR相互作用，TMEM25的缺失允许单体EGFR介导的STAT3的过度激活促进TNBC的进展。
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor outcome and lacks of approved targeted therapy. Overexpression of epidermal growth factor receptor (EGFR) is found in more than 50% TNBC and is suggested as a driving force in progression of TNBC; however, targeting EGFR using antibodies to prevent its dimerization and activation shows no significant benefits for TNBC patients. Here we report that EGFR monomer may activate signal transducer activator of transcription-3 (STAT3) in the absence of transmembrane protein TMEM25, whose expression is frequently decreased in human TNBC. Deficiency of TMEM25 allows EGFR monomer to phosphorylate STAT3 independent of ligand binding, and thus enhances basal STAT3 activation to promote TNBC progression in female mice. Moreover, supplying TMEM25 by adeno-associated virus strongly suppresses STAT3 activation and TNBC progression. Hence, our study reveals a role of monomeric-EGFR/STAT3 signaling pathway in TNBC progression and points out a potential targeted therapy for TNBC. Aberrant EGFR expression is associated with triple-negative breast cancer (TNBC). Here the authors identify that TMEM25 interacts with EGFR and the loss of TMEM25 allows monomeric EGFR-mediated hyperactivation of STAT3 to promote TNBC progression.
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影响因子：
16.6
作者：
Bottos A;Gotthardt D;Gill JW;Gattelli A;Frei A;Tzankov A;Sexl V;Wodnar-Filipowicz A;Hynes NE
通讯作者：
Hynes NE
影响因子：
5.7
作者：
Gajiwala, Ketan S.;Feng, Junli;Stewart, Al
通讯作者：
Stewart, Al
影响因子：
64.5
作者：
Ding, S;Wu, XH;Xu, T
通讯作者：
Xu, T
影响因子：
6.4
作者：
Banerjee K;Resat H
通讯作者：
Resat H
影响因子：
45.3
作者：
Carey, Lisa A.;Rugo, Hope S.;Winer, Eric P.
通讯作者：
Winer, Eric P.