FAK activation is required for IGF1R-mediated regulation of EMT, migration, and invasion in mesenchymal triple negative breast cancer cells
Metrics: PDF 2945 views | HTML 3004 views | ?
LaTonia Taliaferro-Smith1, Elaine Oberlick1,2, Tongrui Liu1, Tanisha McGlothen1, Tiffanie Alcaide1, Rachel Tobin1, Siobhan Donnelly3, Rachel Commander3, Erik Kline1, Ganji Purnachandra Nagaraju1, Lauren Havel1, Adam Marcus1, Rita Nahta3, Ruth O’Regan1,4
1Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322 USA
2Graduate Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115 USA
3Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, 30322 USA
4Georgia Cancer Center for Excellence at Grady Memorial Hospital, Atlanta, GA, 30303 USA
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
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.