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Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance

R I Cordo Russo1, W Béguelin1, M C Díaz Flaqué1

  • 1Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina.

Oncogene
|September 2, 2014
PubMed

Insights

Nuclear ErbB-2 (NErbB-2) drives breast cancer growth and resistance to trastuzumab (Ttzm). Targeting NErbB-2, not just membrane ErbB-2, offers a new strategy to overcome treatment failure in breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Membrane ErbB-2 (MErbB-2) is crucial in breast cancer (BC).
  • Nuclear ErbB-2 (NErbB-2) is a poor prognostic factor in MErbB-2-positive BC.
  • Current therapies like trastuzumab (Ttzm) only target MErbB-2.

Purpose of the Study:

  • To investigate the role of NErbB-2 in BC growth and Ttzm resistance.
  • To identify NErbB-2 as a potential therapeutic target.
  • To elucidate the molecular mechanisms of NErbB-2 action.

Main Methods:

  • Studied BC cell lines sensitive and resistant to Ttzm.
  • Investigated the effect of NErbB-2 blockade on BC cell growth.
  • Analyzed protein phosphorylation and dimer formation (ErbB-2, ErbB-3, Akt).
  • Examined the assembly of transcriptional complexes at the cyclin D1 promoter.
  • Correlated nuclear ErbB-2 and Stat3 interaction with clinical outcomes.

Main Results:

  • Blockade of NErbB-2 abrogated growth in Ttzm-sensitive and resistant BC cells.
  • NErbB-2 inhibition suppressed growth in a preclinical Ttzm-resistant BC model.
  • ErbB-2 forms a nuclear transcriptional complex with Stat3 and ErbB-3, regulating cyclin D1.
  • NErbB-2 is a key proliferation driver in Ttzm-resistant BC.
  • Ttzm resistance is linked to its inability to disrupt the nuclear Stat3/ErbB-2/ErbB-3 complex.
  • Nuclear ErbB-2 and Stat3 interaction correlates with poor survival in primary breast tumors.

Conclusions:

  • NErbB-2 is a critical driver of BC proliferation and Ttzm resistance.
  • The nuclear ErbB-2/Stat3/ErbB-3 complex is a novel target for BC therapy.
  • Targeting NErbB-2 offers a promising strategy to overcome Ttzm resistance.
  • Findings challenge current anti-ErbB-2 drug design paradigms.

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