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


ABSTRACT: The acquisition of endocrine resistance is a common obstacle in endocrine therapy of patients with oestrogen receptor-? (ER?)-positive breast tumours. We previously demonstrated that the BIG3-PHB2 complex has a crucial role in the modulation of oestrogen/ER? signalling in breast cancer cells. Here we report a cell-permeable peptide inhibitor, called ERAP, that regulates multiple ER?-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 ER?, which leads to the inhibition of multiple ER?-signalling pathways, including genomic and non-genomic ER? activation and ER? phosphorylation, and the growth of ER?-positive breast cancer cells both in vitro and in vivo. More importantly, ERAP treatment suppresses tamoxifen resistance and enhances tamoxifen responsiveness in ER?-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.

SUBMITTER: Yoshimaru T 

PROVIDER: S-EPMC3791465 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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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 betw  ...[more]

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