TY - JOUR T1 - Insulin-like growth factor-1 receptor signaling increases the invasive potential of HER2-overexpressing breast cancer cells via Src-FAK and FoxM1 JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.114.095380 SP - mol.114.095380 AU - Eduardo Sanabria-Figueroa AU - Siobhan Donnelly AU - Kevin Foy AU - Meghan Buss AU - Robert C Castellino AU - Ellisavet Paplomata AU - Latonia Taliaferro-Smith AU - Pravin Kaumaya AU - Rita Nahta Y1 - 2014/01/01 UR - http://molpharm.aspetjournals.org/content/early/2014/11/12/mol.114.095380.abstract N2 - Resistance to the HER2-targeted antibody trastuzumab is a major clinical concern in the treatment of HER2-positive metastatic breast cancer. Increased expression or signaling from the insulin-like growth factor-1 receptor (IGF-1R) has been reported to be associated with trastuzumab resistance. However, the specific molecular and biological mechanisms through which IGF-1R promotes resistance or disease progression remain poorly defined. In the current study, we found that the major biological effect promoted by IGF-1R was cellular invasion, which was mediated by both Src-FAK signaling and FoxM1. Co-targeting IGF-1R and HER2 using either IGF-1R antibodies or IGF-1R shRNA in combination with trastuzumab resulted in significant but modest growth inhibition. The most significant biological effect achieved by co-targeting IGF-1R and HER2 in trastuzumab-resistant cells was reduced invasion. Constitutively active Src blocked the anti-invasive effect of IGF-1R/HER2 co-targeted therapy. Further, knockdown of FoxM1 blocked IGF-1-mediated invasion, and dual targeting of IGF-1R and HER2 reduced expression of FoxM1. Re-expression of FoxM1 restored the invasive potential of IGF-1R knockdown cells treated with trastuzumab. Overall, our results strongly indicate that therapeutic combinations that co-target IGF-1R and HER2 may reduce the invasive potential of cancer cells that are resistant to trastuzumab through mechanisms that depend in part on Src and FoxM1. ER -