Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells

Endocrinology. 2003 Mar;144(3):1032-44. doi: 10.1210/en.2002-220620.


The development of acquired resistance to antihormonal agents in breast cancer is a major therapeutic problem. We have developed a tamoxifen-resistant (TAM-R) MCF-7 breast cancer cell line to investigate the mechanisms behind this condition. Both epidermal growth factor receptor (EGFR) and c-erbB2 mRNA and protein expression were increased in TAM-R compared with wild-type MCF-7 cells, whereas comparable levels of c-erbB3 mRNA and protein were expressed in both cell lines. Under basal conditions, phosphorylated EGFR/c-erbB2, EGFR/c-erbB3 but not c-erbB2/c-erbB3 receptor heterodimers were detected in TAM-R cells in association with increased levels of phosphorylated extracellular-signal regulated kinase 1/2 (ERK1/2). Both cell lines were capable of generating a range of EGFR-specific ligands and increased expression of transforming growth factor alpha was observed in TAM-R cells. Treatment of TAM-R cells with ZD1839 (Iressa) or trastuzumab (Herceptin) blocked c-erbB receptor heterodimer formation and phosphorylation, reduced ERK1/2 activity, and strongly inhibited cell growth. The MAPK kinase inhibitor PD098059 specifically reduced phosphorylated ERK1/2 levels and inhibited TAM-R growth. All three agents abolished ERK1/2 activity in wild-type cells but caused only small reductions in cell proliferation. These results demonstrate that TAM-R MCF-7 cell growth is mediated by the autocrine release and action of an EGFR-specific ligand inducing preferential EGFR/c-erbB2 dimerization and downstream activation of the ERK pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / chemistry
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology*
  • Cell Division / drug effects
  • Dimerization*
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / analysis*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Flavonoids / pharmacology
  • Gefitinib
  • Humans
  • Mitogen-Activated Protein Kinase 1 / analysis
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / analysis
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation
  • Quinazolines / pharmacology
  • RNA, Messenger / analysis
  • Receptor, ErbB-2 / analysis*
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Tamoxifen / therapeutic use*
  • Transforming Growth Factor alpha / genetics
  • Trastuzumab
  • Tumor Cells, Cultured


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Flavonoids
  • Quinazolines
  • RNA, Messenger
  • Transforming Growth Factor alpha
  • Tamoxifen
  • ErbB Receptors
  • Receptor, ErbB-2
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Trastuzumab
  • Gefitinib
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one