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

Tetsuro Yoshimaru, Masato Komatsu, Taisuke Matsuo, Yi-An Chen, Yoichi Murakami, Kenji Mizuguchi, Eiichi Mizohata, Tsuyoshi Inoue, Miki Akiyama, Rui Yamaguchi, Seiya Imoto, Satoru Miyano, Yasuo Miyoshi, Mitsunori Sasa, Yusuke Nakamura and Toyomasa Katagiri ()
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Tetsuro Yoshimaru: Institute for Genome Research, The University of Tokushima
Masato Komatsu: Institute for Genome Research, The University of Tokushima
Taisuke Matsuo: Institute for Genome Research, The University of Tokushima
Yi-An Chen: National Institute of Biomedical Innovation
Yoichi Murakami: National Institute of Biomedical Innovation
Kenji Mizuguchi: National Institute of Biomedical Innovation
Eiichi Mizohata: Graduate School of Engineering, Osaka University
Tsuyoshi Inoue: Graduate School of Engineering, Osaka University
Miki Akiyama: Laboratory of Molecular Medicine, University of Tokyo
Rui Yamaguchi: Laboratory of Sequence Analysis, The University of Tokyo
Seiya Imoto: Laboratory of DNA Information Analysis, Human Genome Centre, Institute of Medical Science, The University of Tokyo
Satoru Miyano: Laboratory of DNA Information Analysis, Human Genome Centre, Institute of Medical Science, The University of Tokyo
Yasuo Miyoshi: Hyogo College of Medicine
Mitsunori Sasa: Tokushima Breast Care Clinic
Yusuke Nakamura: Laboratory of Molecular Medicine, University of Tokyo
Toyomasa Katagiri: Institute for Genome Research, The University of Tokushima

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms3443

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