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Targeting BIG3-PHB2 interaction to overcome tamoxifen resistance in breast cancer cells

Tetsuro Yoshimaru1, Masato Komatsu, Taisuke Matsuo

  • 1Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan.

Nature Communications
|September 21, 2013
PubMed

Insights

A novel peptide inhibitor, ERAP, targets the BIG3-PHB2 interaction to overcome endocrine resistance in oestrogen receptor-α (ERα)-positive breast cancer. ERAP enhances tamoxifen responsiveness, offering a new therapeutic strategy for luminal breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Endocrine resistance is a major challenge in treating oestrogen receptor-α (ERα)-positive breast cancer.
  • The BIG3-PHB2 complex is implicated in regulating ERα signaling pathways in breast cancer cells.

Purpose of the Study:

  • To develop a novel therapeutic agent targeting the BIG3-PHB2 interaction.
  • To investigate the efficacy of ERAP in overcoming tamoxifen resistance in ERα-positive breast cancer.

Main Methods:

  • Development of a cell-permeable peptide inhibitor, ERAP.
  • Inhibition of the BIG3-PHB2 interaction using ERAP.
  • Assessment of ERAP's effects on ERα signaling pathways (genomic, non-genomic, phosphorylation) and cell growth in vitro and in vivo.

Main Results:

  • ERAP effectively inhibits the BIG3-PHB2 interaction, releasing PHB2.
  • Released PHB2 binds to ERα, inhibiting multiple ERα signaling pathways and cancer cell growth.
  • ERAP treatment reverses tamoxifen resistance and improves tamoxifen sensitivity in ERα-positive breast cancer models.

Conclusions:

  • Inhibiting the BIG3-PHB2 interaction is a promising therapeutic strategy for ERα-positive breast cancer.
  • ERAP demonstrates potential as a novel treatment to overcome endocrine resistance and enhance tamoxifen efficacy.

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