Epidermal growth factor receptor (EGFR) is transcriptionally induced by the Y-box binding protein-1 (YB-1) and can be inhibited with Iressa in basal-like breast cancer, providing a potential target for therapy

Breast Cancer Res. 2007;9(5):R61. doi: 10.1186/bcr1767.


Introduction: Basal-like breast cancers (BLBCs) are very aggressive, and present serious clinical challenges as there are currently no targeted therapies available. We determined the regulatory role of Y-box binding protein-1 (YB-1) on epidermal growth factor receptor (EGFR) overexpression in BLBC, and the therapeutic potential of inhibiting EGFR. We pursued this in light of our recent work showing that YB-1 induces the expression of EGFR, a new BLBC marker.

Methods: Primary tumour tissues were evaluated for YB1 protein expression by immunostaining tissue microarrays, while copy number changes were assessed by comparative genomic hybridization (CGH). The ability of YB-1 to regulate EGFR was evaluated using luciferase reporter, chromatin immunoprecipitation (ChIP) and gel shift assays. The impact of Iressa on monolayer cell growth was measured using an ArrayScan VTI high-throughput analyser to count cell number, and colony formation in soft agar was used to measure anchorage-independent growth.

Results: YB-1 (27/37 or 73% of cases, P = 3.899 x 10(-4)) and EGFR (20/37 or 57.1% of cases, P = 9.206 x 10(-12)) are expressed in most cases of BLBC. However, they are not typically amplified in primary BLBC, suggesting overexpression owing to transcriptional activation. In support of this, we demonstrate that YB-1 promotes EGFR reporter activity. YB-1 specifically binds the EGFR promoter at two different YB-1-responsive elements (YREs) located at -940 and -968 using ChIP and gel shift assays in a manner that is dependent on the phosphorylation of S102 on YB-1. Inhibiting EGFR with Iressa suppressed the growth of SUM149 cells by approximately 40% in monolayer, independent of mutations in the receptor. More importantly anchorage-independent growth of BLBC cell lines was inhibited with combinations of Iressa and YB-1 suppression.

Conclusion: We have identified for the first time a causal link for the expression of EGFR in BLBC through the induction by YB-1 where it binds specifically to two distinguished YREs. Finally, inhibition of EGFR in combination with suppression of YB-1 presents a potential opportunity for therapy in BLBC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Cell Differentiation
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / metabolism
  • Cell Proliferation
  • Chromatin Immunoprecipitation
  • Electrophoretic Mobility Shift Assay
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Female
  • Gefitinib
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Luciferases / metabolism
  • Nucleic Acid Hybridization
  • Phosphorylation
  • Quinazolines / pharmacology*
  • Receptor, ErbB-2 / metabolism
  • Tissue Array Analysis
  • Y-Box-Binding Protein 1 / pharmacology*


  • Antineoplastic Agents
  • Quinazolines
  • Y-Box-Binding Protein 1
  • Luciferases
  • ErbB Receptors
  • Receptor, ErbB-2
  • Gefitinib