Abstract
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.
Highlights
Integrin signaling may drive breast carcinoma resistance to apoptosis-inducing and anti-HER2 agents[13,14], implying that β 4 integrin signaling is important in the development of breast cancer malignancy
The interaction between β 4 integrin and FAK was identified in the malignant triple-negative breast cancer cell line (MDA-MB-231) (Fig. 1a) as well as in the metastatic colon cancer cell line (HCT-116), but not in the non-tumorigenic breast epithelial cell line (MCF10A) or other cancer cell lines (i.e., MCF7, MDA-MB-435, A549, and HeLa)
We observed that β 4 integrin and FAK were co-localized in the plasma membrane or protrusions of metastatic breast MDA-MB-231 cells in contrast to that observed in the non-metastatic breast MCF7 cells (Fig. 1b)
Summary
Integrin signaling may drive breast carcinoma resistance to apoptosis-inducing and anti-HER2 agents[13,14], implying that β 4 integrin signaling is important in the development of breast cancer malignancy. It is generally reported that overexpression and auto-phosphorylation of FAK are involved in the development of malignancy in various cancers[18,19]. Accumulating evidence indicates that overexpression of β 4 integrin or FAK is intimately associated with the malignancy of breast cancer[11,24]. Recent studies by Abdel-Ghany et al revealed that β 4 integrin enables the modulation of FAK-mediated signaling during the regulation of β 4 integrin-dependent tumorigenesis and malignancy[25]. We illustrate a molecular signaling cascade in which the EGF-Src-β 4 integrin axis physically recruits and activates FAK activity and downstream signaling, thereby facilitating the progression of breast cancer towards malignancies
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