Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance. Academic Article uri icon

Overview

abstract

  • Membrane overexpression of ErbB-2/HER2 receptor tyrosine kinase (membrane ErbB-2 (MErbB-2)) has a critical role in breast cancer (BC). We and others have also shown the role of nuclear ErbB-2 (NErbB-2) in BC, whose presence we identified as a poor prognostic factor in MErbB-2-positive tumors. Current anti-ErbB-2 therapies, as with the antibody trastuzumab (Ttzm), target only MErbB-2. Here, we found that blockade of NErbB-2 action abrogates growth of BC cells, sensitive and resistant to Ttzm, in a scenario in which ErbB-2, ErbB-3 and Akt are phosphorylated, and ErbB-2/ErbB-3 dimers are formed. Also, inhibition of NErbB-2 presence suppresses growth of a preclinical BC model resistant to Ttzm. We showed that at the cyclin D1 promoter, ErbB-2 assembles a transcriptional complex with Stat3 (signal transducer and activator of transcription 3) and ErbB-3, another member of the ErbB family, which reveals the first nuclear function of ErbB-2/ErbB-3 dimer. We identified NErbB-2 as the major proliferation driver in Ttzm-resistant BC, and demonstrated that Ttzm inability to disrupt the Stat3/ErbB-2/ErbB-3 complex underlies its failure to inhibit growth. Furthermore, our results in the clinic revealed that nuclear interaction between ErbB-2 and Stat3 correlates with poor overall survival in primary breast tumors. Our findings challenge the paradigm of anti-ErbB-2 drug design and highlight NErbB-2 as a novel target to overcome Ttzm resistance.

publication date

  • September 1, 2014

Research

keywords

  • Antibodies, Monoclonal, Humanized
  • Breast Neoplasms
  • Cell Proliferation
  • Drug Resistance, Neoplasm
  • Molecular Targeted Therapy
  • Mutant Proteins
  • Receptor, ErbB-2

Identity

Scopus Document Identifier

  • 84933050068

Digital Object Identifier (DOI)

  • 10.1038/onc.2014.272

PubMed ID

  • 25174405

Additional Document Info

volume

  • 34

issue

  • 26