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

// LaTonia Taliaferro-Smith 1 , Elaine Oberlick 1, 2 , Tongrui Liu 1 , Tanisha McGlothen 1 , Tiffanie Alcaide 1 , Rachel Tobin 1 , Siobhan Donnelly 3 , Rachel Commander 3 , Erik Kline 1 , Ganji Purnachandra Nagaraju 1 , Lauren Havel 1 , Adam Marcus 1 , Rita Nahta 3 , Ruth O’Regan 1, 4 1 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322 USA 2 Graduate Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115 USA 3 Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, 30322 USA 4 Georgia Cancer Center for Excellence at Grady Memorial Hospital, Atlanta, GA, 30303 USA Correspondence to: LaTonia Taliaferro-Smith, e-mail: Ltsmit3@emory.edu Keywords: Triple-negative breast cancers (TNBC), insulin-like growth factor 1 receptor (IGF1R), focal adhesion kinase (FAK), epithelial-mesenchymal transition (EMT), invasion Received: December 06, 2014      Accepted: December 31, 2014      Published: February 28, 2015 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.