title: Co-inhibition of epidermal growth factor receptor and insulin-like growth factor receptor 1 enhances radiosensitivity in human breast cancer cells.
abstract: BACKGROUND
  Over-expression of epidermal growth factor receptor (EGFR) or insulin-like growth factor-1 receptor (IGF-1R) have been shown to closely correlate with radioresistance of breast cancer cells. This study aimed to investigate the impact of co-inhibition of EGFR and IGF-1R on the radiosensitivity of two breast cancer cells with different profiles of EGFR and IGF-1R expression.
  
  
  METHODS
  The MCF-7 (EGFR +/-, IGF-1R +++) and MDA-MB-468 (EGFR +++, IGF-1R +++) breast cancer cell lines were used. Radiosensitizing effects were determined by colony formation assay. Apoptosis and cell cycle distribution were measured by flow cytometry. Phospho-Akt and phospho-Erk1/2 were quantified by western blot. In vivo studies were conducted using MDA-MB-468 cells xenografted in nu/nu mice.
  
  
  RESULTS
  In MDA-MB-468 cells, the inhibition of IGF-1R upregulated the p-EGFR expression. Either EGFR (AG1478) or IGF-1R inhibitor (AG1024) radiosensitized MDA-MB-468 cells. In MCF-7 cells, radiosensitivity was enhanced by AG1024, but not by AG1478. Synergistical radiosensitizing effect was observed by co-inhibition of EGFR and IGF-1R only in MDA-MB-468 cells with a DMF10% of 1.90. The co-inhibition plus irradiation significantly induced more apoptosis and arrested the cells at G0/G1 phase in MDA-MB-468 cells. Only co-inhibition of EGFR and IGF-1R synergistically diminished the expression of p-Akt and p-Erk1/2 in MDA-MB-468 cells. In vivo studies further verified the radiosensitizing effects by co-inhibition of both pathways in a MDA-MB-468 xenograft model.
  
  
  CONCLUSIONS
  Our data suggested that co-inhibition of EGFR and IGF-1R synergistically radiosensitized breast cancer cells with both EGFR and IGF-1R high expression. The approach may have an important therapeutic implication in the treatment of breast cancer patients with high expression of EGFR and IGF-1R.
authors.affiliation: Department of Radiation Oncology, Sixth People's Hospital of Jiao Tong University, 600 Yi Shan Rd,, Shanghai 200233, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Marlon R
authors.initials: MR
authors.lastname: Veldwijk
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Zhao-Bin
authors.initials: ZB
authors.lastname: Li
authors.forename: Wen-Cai
authors.initials: WC
authors.lastname: Xu
authors.forename: Shen
authors.initials: S
authors.lastname: Fu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001943:Breast Neoplasms / Q000532:radiotherapy*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D011836:Radiation Tolerance / Q000187:drug effects*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D014410:Tumor Stem Cell Assay; D020032:Tyrphostins / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; C447031:tyrphostin AG 1024; C101044:RTKI cpd; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt