Therapeutic advances in BIG3-PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer.

Cancer Science
Tetsuro YoshimaruToyomasa Katagiri

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 gr...Continue Reading

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Citations

May 31, 2017·Nature Communications·Tetsuro YoshimaruToyomasa Katagiri
Nov 21, 2017·NPJ Precision Oncology·Roudy Chiminch Ekyalongo, Douglas Yee
Jul 22, 2021·Journal of Human Genetics·Tetsuro YoshimaruToyomasa Katagiri

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Methods Mentioned

BETA
flow cytometry
xenograft
xenografts

Software Mentioned

CellQuest

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