SHC4 orchestrates β-catenin pathway-mediated metastasis in triple-negative breast cancer by promoting Src kinase autophosphorylation

三阴性乳腺癌 癌症研究 自磷酸化 Wnt信号通路 原癌基因酪氨酸蛋白激酶Src 转移 CD44细胞 下调和上调 生物 信号转导 连环素 激酶 乳腺癌 癌症 细胞生物学 蛋白激酶A 体外 基因 生物化学 遗传学
作者
Wenjing Zhong,Yunting Jian,Chao Zhang,Yue Li,Zhongyu Yuan,Zhenchong Xiong,Weiling Huang,Ying Ouyang,Xiangfu Chen,Libing Song,Pian Liu,Xi Wang
出处
期刊:Cancer Letters [Elsevier]
卷期号:582: 216516-216516 被引量:3
标识
DOI:10.1016/j.canlet.2023.216516
摘要

Triple-negative breast cancer (TNBC) is highly aggressive and metastatic, and has the poorest prognosis among all breast cancer subtypes. Activated β-catenin is enriched in TNBC and involved in Wnt signaling-independent metastasis. However, the underlying mechanisms of β-catenin activation in TNBC remain unknown. Here, we found that SHC4 was upregulated in TNBC and high SHC4 expression was significantly correlated with poor outcomes. Overexpression of SHC4 promoted TNBC aggressiveness in vitro and facilitated TNBC metastasis in vivo. Mechanistically, SHC4 interacted with Src and maintained its autophosphorylated activation, which activated β-catenin independent of Wnt signaling, and finally upregulated the transcription and expression of its downstream genes CD44 and MMP7. Furthermore, we determined that the PxPPxPxxxPxxP sequence on CH2 domain of SHC4 was critical for SHC4-Src binding and Src kinase activation. Overall, our results revealed the mechanism of β-catenin activation independent of Wnt signaling in TNBC, which was driven by SHC4-induced Src autophosphorylation, suggesting that SHC4 might be a potential prognostic marker and therapeutic target in TNBC.
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