PT  - JOURNAL ARTICLE
AU  - Eduardo Sanabria-Figueroa
AU  - Siobhan M. Donnelly
AU  - Kevin C. Foy
AU  - Meghan C. Buss
AU  - Robert C. Castellino
AU  - Elisavet Paplomata
AU  - Latonia Taliaferro-Smith
AU  - Pravin T.P. Kaumaya
AU  - Rita Nahta
TI  - Insulin-Like Growth Factor-1 Receptor Signaling Increases the Invasive Potential of Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer Cells via Src-Focal Adhesion Kinase and Forkhead Box Protein M1
AID  - 10.1124/mol.114.095380
DP  - 2015 Feb 01
TA  - Molecular Pharmacology
PG  - 150--161
VI  - 87
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/87/2/150.short
4100  - http://molpharm.aspetjournals.org/content/87/2/150.full
SO  - Mol Pharmacol2015 Feb 01; 87
AB  - Resistance to the human epidermal growth factor receptor (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 biologic mechanisms through which IGF-1R promotes resistance or disease progression remain poorly defined. In this study, we found that the major biologic effect promoted by IGF-1R was invasion, which was mediated by both Src-focal adhesion kinase (FAK) signaling and Forkhead box protein M1 (FoxM1). Cotargeting IGF-1R and HER2 using either IGF-1R antibodies or IGF-1R short hairpin RNA in combination with trastuzumab resulted in significant but modest growth inhibition. Reduced invasion was the most significant biologic effect achieved by cotargeting IGF-1R and HER2 in trastuzumab-resistant cells. Constitutively active Src blocked the anti-invasive effect of IGF-1R/HER2 cotargeted therapy. Furthermore, 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 cotarget 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.