Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin

Oncogene. 2005 Jun 30;24(28):4540-8. doi: 10.1038/sj.onc.1208658.


An emerging paradigm holds that loss of negative signalling to receptor tyrosine kinases (RTKs) is permissive for their oncogenic activity. Herein, we have addressed tumor suppression by RALT/MIG-6, a transcriptionally controlled feedback inhibitor of ErbB RTKs, in breast cancer cells. Knockdown of RALT expression by RNAi enhanced the EGF-dependent proliferation of normal breast epithelial cells, indicating that loss of RALT signalling in breast epithelium may represent an advantageous condition during ErbB-driven tumorigenesis. Although mutational inactivation of the RALT gene was not detected in human breast carcinomas, RALT mRNA and protein expression was strongly and selectively reduced in ERBB2-amplified breast cancer cell lines. Reconstitution of RALT expression in ERBB2-amplified SKBr-3 and BT474 cells inhibited ErbB-2-dependent mitogenic signalling and counteracted the ability of ErbB ligands to promote resistance to the ErbB-2-targeting drug Herceptin. Thus, loss of RALT expression cooperates with ERBB2 gene amplification to drive full oncogenic signalling by the ErbB-2 receptor. Moreover, loss of RALT signalling may adversely affect tumor responses to ErbB-2-targeting agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / drug effects
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Carcinoma / genetics*
  • Carcinoma / pathology
  • Cell Line, Tumor
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm / genetics
  • Epidermal Growth Factor / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Loss of Heterozygosity
  • Receptor, ErbB-2 / genetics*
  • Receptor, ErbB-2 / metabolism
  • Signal Transduction
  • Trastuzumab
  • Tumor Suppressor Proteins


  • Adaptor Proteins, Signal Transducing
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • ERRFI1 protein, human
  • Tumor Suppressor Proteins
  • Epidermal Growth Factor
  • Receptor, ErbB-2
  • Extracellular Signal-Regulated MAP Kinases
  • Trastuzumab