FAK activation is required for IGF1R-mediated regulation of EMT, migration, and invasion in mesenchymal triple negative breast cancer cells

Abstract

Triple negative breast cancer (TNBC) is a highly metastatic disease that currently lacks effective prevention and treatment strategies. The insulin-like growth factor 1 receptor (IGF1R) and focal adhesion kinase (FAK) signaling pathways function in numerous developmental processes, and alterations in both are linked with a number of common pathological diseases. Overexpression of IGF1R and FAK are closely associated with metastatic breast tumors. The present study investigated the interrelationship between IGF1R and FAK signaling in regulating the malignant properties of TNBC cells. Using small hairpin RNA (shRNA)-mediated IGF1R silencing methods, we showed that IGF1R is essential for sustaining mesenchymal morphologies of TNBC cells and modulates the expression of EMT-related markers. We further showed that IGF1R overexpression promotes migratory and invasive behaviors of TNBC cell lines. Most importantly, IGF1R-driven migration and invasion is predominantly mediated by FAK activation and can be suppressed using pharmacological inhibitors of FAK. Our findings in TNBC cells demonstrate a novel role of the IGF1R/FAK signaling pathway in regulating critical processes involved in the metastatic cascade. These results may improve the current understanding of the basic molecular mechanisms of TNBC metastasis and provide a strong rationale for co-targeting of IGF1R and FAK as therapy for mesenchymal TNBCs.

IGF-I/EGF and E2 signaling crosstalk through IGF-IR conduit point affects breast cancer cell adhesion

“…Moreover, Zheng et al, 2009 [91] show that the FERM domain of FAK can bind to the β subunit of IGF-IR. FAK activation is necessary for IGF-IR mediated regulation of EMT and regulation of motility properties of triple negative breast cancer cells [94]. In this study FAK and IGF-IR were found to colocalize in MCF-7 cells.…”

Function of insulin‑like growth factor 1 receptor in cancer resistance to chemotherapy (Review)

“…IGF1R is associated with multiple signaling pathways via downstream proteins, including IRS and PI3K (38)(39)(40). IGF1R, which mediates apoptosis-inhibiting signals, and enhances cell metabolism and protein synthesis via downstream mechanistic target of rapamycin (MTOR) kinase signaling, activates the PI3K/AKT signaling pathway (41)(42)(43).…”

“…The crosstalk between IGF1R and focal adhesion kinase (FAK) signaling pathways (38), IGF1R and the classical Wnt signaling pathways (48,49), and IGF1R and transforming growth factor β (TGFβ) signaling pathways have also been further clarified (50). In addition, certain IGF1R signals have been newly identified, namely RTK heterodimers, including the INSR hybrid receptor, and IGF1R/INSR that function as dependent receptors intervening in IGF1R signaling and its regulation (51).…”

“…FAK, a substrate protein of IGF1R, is activated by integrin, affecting epithelial transformation, invasion and metastasis of tumor cells IGF1R-independently (38). Extracellular fibronectin increases the activity of β1 integrin to increase the abundance of MAPK-phosphatase-1 and the receptor of activated C kinase (RACK-1) (62).…”

Novel therapeutic strategies for patients with triple-negative breast cancer

“…Down-regulation of IGF1R depending on focal adhesion kinase (FAK) regulated the epithelial-to-mesenchymal transition and suppressed colony formation, migration, and invasion of TNBC via the IGF1R/FAK signaling axis, suggesting that co-targeting of IGF1R and FAK could act as therapy markers for MES TNBCs through the IGF1R/FAK signaling pathway 103. The article by Cerqueira et al104 has addressed that high levels of CIP4 expression promoted metastasis of TNBC, while knockdown of CIP4 led to had no overt effect on tumor growth but observably suppressed the incidence of TNBC cell invasion in vitro and tumor metastasis in vivo through EGFR/CIP4/Erk/MMP-2 signaling pathway, which demonstrated that targeting CIP4 will become a poor prognostic marker in TNBC.…”