Tai Yu-Ling, Chu Pei-Yu, Lai I-Rue, Wang Ming-Yang, Tseng Hui-Yuan, Guan Jun-Lin, Liou Jun-Yang, Shen Tang-Long
Department of Plant Pathology and Microbiology, National Taiwan University, Taipei 10617, Taiwan.
Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
Sci Rep. 2015 Nov 9;5:16408. doi: 10.1038/srep16408.
β4 integrin and focal adhesion kinase (FAK) are often associated with a poor prognosis in cancer patients, and their signaling events have recently been linked to malignant outcomes. Here, we demonstrate, for the first time, physical and functional interactions between β4 integrin and FAK that influence breast cancer malignancy. An amino-terminal linker within FAK is essential for its binding with the cytodomain of β4 integrin. Moreover, EGFR/Src-signaling triggers the tyrosine phosphorylation of β4 integrin, which, in turn, recruits FAK to β4 integrin and leads to FAK activation and signaling. Upon disruption of the β4 integrin/FAK complex, tumorigenesis and metastasis in triple-negative breast cancer were markedly reduced. Importantly, the concomitant overexpression of β4 integrin and FAK significantly correlates with malignant potential in patients with triple-negative breast cancer. This study describes a pro-metastatic EGFR/Src-dependent β4 integrin/FAK complex that is involved in breast cancer malignancy and is a novel therapeutic target for triple-negative breast cancer.
β4整合素和粘着斑激酶（FAK）在癌症患者中常与不良预后相关，且它们的信号转导事件最近已与恶性结局联系起来。在此，我们首次证明了β4整合素与FAK之间的物理和功能相互作用会影响乳腺癌的恶性程度。FAK内的一个氨基末端连接子对于其与β4整合素胞质结构域的结合至关重要。此外，表皮生长因子受体（EGFR）/Src信号转导触发β4整合素的酪氨酸磷酸化，这反过来又将FAK招募至β4整合素并导致FAK激活和信号转导。破坏β4整合素/FAK复合物后，三阴性乳腺癌的肿瘤发生和转移明显减少。重要的是，β4整合素和FAK的共表达与三阴性乳腺癌患者的恶性潜能显著相关。本研究描述了一种促转移的、依赖EGFR/Src的β4整合素/FAK复合物，其参与乳腺癌的恶性程度，是三阴性乳腺癌的一个新的治疗靶点。
