Therapeutic advances in BIG3‐PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer |
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| Authors: | Tetsuro Yoshimaru Masato Komatsu Yasuo Miyoshi Junko Honda Mitsunori Sasa Toyomasa Katagiri |
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| Affiliation: | 1. Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima, Japan;2. Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Hyogo, Japan;3. Department of Surgery, National Hospital Organization Higashitokushima Medical Center, Tokushima, Japan;4. Department of Surgery, Tokushima Breast Care Clinic, Tokushima, Japan |
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| Abstract: | 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. |
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| Keywords: | Crosstalk estrogen growth factor PHB2 tamoxifen‐resistance |
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