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

Oncogene volume 24, pages 4540–4548 (2005)Cite this article

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.

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Acknowledgements

We thank M Fanciulli, S Giordano, N Hynes and G Piaggio for reagents, R Carsetti for cell sorting, S Alemà, D Birnbaum, PG Natali and S Soddu for discussion, R Fraioli for assistance. This work was supported by AIRC and FIRB grants to OS; G. Russo is supported by AIRC.

Author information

Author notes

  1. Gianluca Sala

    Present address: Laboratory of Molecular Oncology, Aging Research Center, Chieti, Italy

  2. Chen Huiping

    Present address: Washington University School of Medicine, St Louis, MO, USA

  3. Sergio Anastasi and Gianluca Sala: These two authors contributed equally to this work

Authors and Affiliations

  1. Laboratory of Immunology, Regina Elena Cancer Institute, via Delle Messi d'Oro, 156/158, 00158, Rome, Italy

    Sergio Anastasi, Gianluca Sala, Fabiana Lucini & Oreste Segatto

  2. Institute for Experimental Pathology, University of Iceland at Keldur, Reykjavik, Iceland

    Chen Huiping & Sigurdur Ingvarsson

  3. Laboratory of Molecular Oncology, IDI, Rome, Italy

    Elisabetta Caprini & Giandomenico Russo

  4. Laboratory of Molecular Oncogenesis, Regina Elena Cancer Institute, via Delle Messi d'Oro, 156/158, 00158, Rome, Italy

    Stefano Iacovelli

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  1. Sergio Anastasi
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Correspondence to Oreste Segatto.

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Supplementary Information accompanies the paper on Oncogene websitge (http://www.nature.com/onc)

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Anastasi, S., Sala, G., Huiping, C. et al. Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin. Oncogene 24, 4540–4548 (2005). https://doi.org/10.1038/sj.onc.1208658

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