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 journalArticle

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

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Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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