HOMER3 facilitates growth factor-mediated β-Catenin tyrosine phosphorylation and activation to promote metastasis in triple negative breast cancer.
HOMER3 facilitates growth factor-mediated β-Catenin tyrosine phosphorylation and activation to promote metastasis in triple negative breast cancer.
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HOMER3 促进生长因子介导的β-连环蛋白酪氨酸磷酸化和激活，以促进三阴性乳腺癌的转移
DOI：
10.1186/s13045-020-01021-x
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发表时间：
2021-01-06
影响因子：
28.5
通讯作者：
Lin C
中科院分区：
文献类型：
--
作者：
Liu Q;He L;Li S;Li F;Deng G;Huang X;Yang M;Xiao Y;Chen X;Ouyang Y;Chen J;Wu X;Wang X;Song L;Lin C
Homer家族支架蛋白(Hmer 1-3)通过调节信号转导复合体的组装来响应外界刺激，在人类疾病的发生和发展中发挥关键作用。然而，荷马蛋白在乳腺癌中的作用仍不清楚。采用免疫组织化学方法检测乳腺癌组织中Hmer-3的表达，Kaplan-Meier生存分析评价其在预后中的意义。通过TOP/FOP闪光报告、酪氨酸磷酸化实验和相互免疫沉淀(IP)实验，分析Hmer 3在生长因子诱导的β-连环蛋白活化中的作用。通过细胞功能测定和小鼠肿瘤模型研究Hmer 3在乳腺癌转移中的作用。在此，我们发现，在这三种HOMER蛋白中，Hmer 3选择性地在最具侵袭性的三阴性乳腺癌(TNBC)亚型中过表达，并与较早的肿瘤转移和较短的患者生存期显著相关。机制上，Hmer 3与c-Src和β-连环蛋白相互作用，从而提供了一个支架平台，以促进生长因子刺激下c-Src诱导的β-连环蛋白酪氨酸磷酸化。Hmer 3促进β-连环蛋白的核转位和激活，这一轴与临床相关。在体外和体内，Hmer 3促进EGF诱导的TNBC细胞的侵袭和转移，并对其起着至关重要的作用。这些发现确定了Hmer 3在生长因子介导的β-连环蛋白激活的转导中的新作用，并提示Hmer 3可能是TNBC的靶向易损性。
HOMER family scaffolding proteins (HOMER1-3) play critical roles in the development and progression of human disease by regulating the assembly of signal transduction complexes in response to extrinsic stimuli. However, the role of HOMER protein in breast cancer remains unclear. HOMER3 expression was examined by immunohistochemistry in breast cancer patient specimens, and its significance in prognosis was assessed by Kaplan–Meier survival analysis. The effects of HOMER3 in growth factor-induced β-Catenin activation were analyzed by assays such as TOP/FOP flash reporter, tyrosine phosphorylation assay and reciprocal immunoprecipitation (IP) assay. Role of HOMER3 in breast cancer metastasis was determined by cell function assays and mice tumor models. Herein, we find that, among the three HOMER proteins, HOMER3 is selectively overexpressed in the most aggressive triple negative breast cancer (TNBC) subtype, and significantly correlates with earlier tumor metastasis and shorter patient survival. Mechanismly, HOMER3 interacts with both c-Src and β-Catenin, thus providing a scaffolding platform to facilitate c-Src-induced β-Catenin tyrosine phosphorylation under growth factor stimulation. HOMER3 promotes β-Catenin nuclear translocation and activation, and this axis is clinically relevant. HOMER3 promotes and is essential for EGF-induced aggressiveness and metastasis of TNBC cells both in vitro and in vivo. These findings identify a novel role of HOMER3 in the transduction of growth factor-mediated β-Catenin activation and suggest that HOMER3 might be a targetable vulnerability of TNBC.
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影响因子：
5.5
作者：
Wahba HA;El-Hadaad HA
通讯作者：
El-Hadaad HA
影响因子：
4.8
作者：
Knight C;James S;Kuntin D;Fox J;Newling K;Hollings S;Pennock R;Genever P
通讯作者：
Genever P
影响因子：
11.4
作者：
Kajiguchi, T.;Chung, E. J.;Trepel, J. B.
通讯作者：
Trepel, J. B.
影响因子：
8.4
作者：
Fan, Ping;Cunliffe, Heather E.;Griffith, Obi L.;Agboke, Fadeke A.;Ramos, Pilar;Gray, Joe W.;Jordan, V. Craig
通讯作者：
Jordan, V. Craig
影响因子：
64.8
作者：
Brakeman, PR;Lanahan, AA;Worley, PF
通讯作者：
Worley, PF