An EGFR/Src-dependent beta 4 integrin/FAK complex contributes to malignancy of breast cancer

beta 4 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 beta 4 integrin and FAK that influence breast cancer malignancy. An amino-terminal linker within FAK is essential for its binding with the cytodomain of beta 4 integrin. Moreover, EGFR/Src-signaling triggers the tyrosine phosphorylation of beta 4 integrin, which, in turn, recruits FAK to beta 4 integrin and leads to FAK activation and signaling. Upon disruption of the beta 4 integrin/FAK complex, tumorigenesis and metastasis in triple-negative breast cancer were markedly reduced. Importantly, the concomitant overexpression of beta 4 integrin and FAK significantly correlates with malignant potential in patients with triple-negative breast cancer. This study describes a pro-metastatic EGFR/Src-dependent beta 4 integrin/FAK complex that is involved in breast cancer malignancy and is a novel therapeutic target for triple-negative breast cancer