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

• Type of Material: Article
• Authors: Latonia Smith, Emory University; Elaine Oberlick, Emory University; Tongrui Lui, Emory University; Trishna McGlothen, Emory University; Tiffanie Alcaide, Emory University; Rachel Tobin, Emory University; Siobhan Donnelly, Emory University; Rachel Commander, Emory University; Eric Kline, Emory University; P Nagaraju Ganji, Emory University; Lauren Havel, Emory University; Adam I Marcus, Emory University; Rita Nahta, Emory University; Ruth O'Regan, Emory University
• Language: English
• Date: 2015-03-10
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Taliaferro-Smith et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=issue&op=view&path[]=106
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 6
• Issue: 7
• Start Page: 4757
• End Page: 4772
• Grant/Funding Information: Research reported in this publication was supported in part by the Integrated Cell Imaging (ICI) core of Winship Cancer Institute of Emory University, NIH/NCI under award number P30CA138292, the Glenn Family Foundation (R.M. O'Regan), R01CA157754 (R. Nahta), and the Emory University FIRST Postdoctoral Fellowship (NIH Grant Number-K12 GM000680) (T.Z. McGlothen)
• Keywords: epithelial-mesenchymal transition (EMT); Triple-negative breast cancers (TNBC); invasion; insulin-like growth factor 1 receptor (IGF1R); focal adhesion kinase (FAK)
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology

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.