Therapeutic advances in BIG3-PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer.
Our previous studies demonstrated that specific inhibition of the BIG3-PHB2 complex, which is a critical modulator in estrogen (E2) signaling, using ERAP, a dominant negative peptide inhibitor, leads to suppression of E2-dependent estrogen receptor (ER) alpha activation through the reactivation of the tumor suppressive activity of PHB2. Here, we report that ERAP has significant suppressive effects against synergistic activation caused by the crosstalk between E2 and growth factors associated with intrinsic or acquired resistance to anti-estrogen tamoxifen in breast cancer cells. Intrinsic PHB2 released from BIG3 by ERAP effectively disrupted each interaction of membrane-associated ERα and insulin-like growth factor 1 receptor beta (IGF-1Rβ), EGFR, PI3K or human epidermal growth factor 2 (HER2) in the presence of E2 and the growth factors IGF or EGF, followed by inhibited the activation of IGF-1Rβ, EGFR or HER2, and reduced Akt, MAPK and ERα phosphorylation levels, resulting in significant suppression of proliferation of ERα-positive breast cancer cells in vitro and in vivo. More importantly, combined treatment with ERAP and tamoxifen led to a synergistic suppression of signaling that was activated by crosstalk between E2 and growth factors or HER2 amplification. Taken together, our findings suggest that the specific inhibition of BIG3-PHB2 is a novel potential therapeutic approach for the treatment of tamoxifen-resistant breast cancers activated by the crosstalk between E2 and growth factor signaling, especially in premenopausal women.
Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima, Japan.
Tetsuro
T
Yoshimaru
Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima, Japan.
Masato
M
Komatsu
Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Hyogo, Japan.
Yasuo
Y
Miyoshi
Department of Surgery, National Hospital Organization Higashitokushima Medical Center, Tokushima, Japan.
Junko
J
Honda
Department of Surgery, Tokushima Breast Care Clinic, Tokushima, Japan.
Mitsunori
M
Sasa
Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima, Japan.
Toyomasa
T
Katagiri
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D010766:Phosphorylation / Q000187:drug effects; D000091402:Prohibitins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D057846:Cell-Penetrating Peptides; D047628:Estrogen Receptor alpha; D020662:Guanine Nucleotide Exchange Factors; D007334:Insulin-Like Growth Factor I; D000091402:Prohibitins; D018719:Erb-b2 Receptor Tyrosine Kinases; D012097:Repressor Proteins; D013629:Tamoxifen; C000595370:ARFGEF3 protein, human; C000600516:ERAP peptide; C506487:ESR1 protein, human; C000717331:PHB2 protein, human; C000717333:Phb2 protein, mouse; C508053:ERBB2 protein, human
Crosstalk; PHB2; estrogen; growth factor; tamoxifen-resistance