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

Sergio Anastasi, Gianluca Sala, Chen Huiping, Elisabetta Caprini, Giandomenico Russo, Stefano Iacovelli, Fabiana Lucini, Sigurdur Ingvarsson, Oreste Segatto

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)4540-4548
Number of pages9
JournalOncogene
Volume24
Issue number28
DOIs
Publication statusPublished - Jun 30 2005

Keywords

  • Breast cancer
  • ErbB-2
  • Herceptin
  • MIG-6
  • RALT
  • Targeted therapies

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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