Targeting BIG3-PHB2 interaction to overcome tamoxifen resistance in breast cancer cells.
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.
Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan.
Tetsuro
T
Yoshimaru
Masato
M
Komatsu
Taisuke
T
Matsuo
Yi-An
YA
Chen
Yoichi
Y
Murakami
Kenji
K
Mizuguchi
Eiichi
E
Mizohata
Tsuyoshi
T
Inoue
Miki
M
Akiyama
Rui
R
Yamaguchi
Seiya
S
Imoto
Satoru
S
Miyano
Yasuo
Y
Miyoshi
Mitsunori
M
Sasa
Yusuke
Y
Nakamura
Toyomasa
T
Katagiri
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D057846:Cell-Penetrating Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D010766:Phosphorylation; D000091402:Prohibitins; D011485:Protein Binding / Q000187:drug effects; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology*
D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; C000600516:ERAP peptide; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047908:Intracellular Signaling Peptides and Proteins; C000717331:PHB2 protein, human; D000091402:Prohibitins; D012097:Repressor Proteins; D020845:Selective Estrogen Receptor Modulators; C502547:WDR5 protein, human; D013629:Tamoxifen; D011495:Histone-Lysine N-Methyltransferase