Journal Article

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

Katagiri, Toyomasa, Akiyama, Miki, Inoue, Tsuyoshi, Mizohata, Eiichi, Yoshimaru, Tetsuro, Komatsu, Masato, Miyano, Satoru, Miyoshi, Yasuo, Imoto, Seiya, Nakamura, Yusuke, Murakami, Yoichi, Sasa, Mitsunori, Yamaguchi, Rui, Matsuo, Taisuke, Chen, Yi-An, Mizuguchi, Kenji

2013

Overview

The acquisition of endocrine resistance is a common obstacle in endocrine therapy of patients with oestrogen receptor-α (ERα)-positive breast tumours. We previously demonstrated that the BIG3–PHB2 complex has a crucial role in the modulation of oestrogen/ERα signalling in breast cancer cells. Here we report a cell-permeable peptide inhibitor, called ERAP, that regulates multiple ERα-signalling pathways associated with tamoxifen resistance in breast cancer cells by inhibiting the interaction between BIG3 and PHB2. Intrinsic PHB2 released from BIG3 by ERAP directly binds to both nuclear- and membrane-associated ERα, which leads to the inhibition of multiple ERα-signalling pathways, including genomic and non-genomic ERα activation and ERα phosphorylation, and the growth of ERα-positive breast cancer cells both in vitro and in vivo . More importantly, ERAP treatment suppresses tamoxifen resistance and enhances tamoxifen responsiveness in ERα-positive breast cancer cells. These findings suggest inhibiting the interaction between BIG3 and PHB2 may be a new therapeutic strategy for the treatment of luminal-type breast cancer. Oestrogen receptor-α (ERα) signalling has a role in breast cancer drug resistance. Here, the authors report a synthetic peptide that disrupts the interaction between the signalling molecules BIG3 and PHB2, and thereby suppresses tamoxifen resistance.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
• Subject: 631/67/1059/2326 / 631/67/1059/602 / 631/67/1347 / Amino Acid Sequence / Antineoplastic Agents - chemical synthesis / Antineoplastic Agents - pharmacology / Binding Sites / Breast cancer / Cell Line, Tumor / Cell Membrane - drug effects / Cell Membrane - metabolism / Cell Nucleus - drug effects / Cell Nucleus - metabolism / Cell-Penetrating Peptides - chemical synthesis / Cell-Penetrating Peptides - pharmacology / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Estrogen Receptor alpha - genetics / Estrogen Receptor alpha - metabolism / Female / Gene Expression Regulation, Neoplastic / Histone-Lysine N-Methyltransferase - antagonists & inhibitors / Histone-Lysine N-Methyltransferase - genetics / Histone-Lysine N-Methyltransferase - metabolism / Humanities and Social Sciences / Humans / Molecular Sequence Data / multidisciplinary / Phosphorylation / Protein Binding - drug effects / Repressor Proteins - antagonists & inhibitors / Repressor Proteins - genetics / Repressor Proteins - metabolism / Science / Science (multidisciplinary) / Selective Estrogen Receptor Modulators - pharmacology / Signal Transduction / Tamoxifen - pharmacology