EZH2-mediated PP2A inactivation confers resistance to HER2-targeted breast cancer therapy

Nature Communications
Yi BaoQiang Yu

Abstract

HER2-targeted therapy has yielded a significant clinical benefit in patients with HER2+ breast cancer, yet disease relapse due to intrinsic or acquired resistance remains a significant challenge in the clinic. Here, we show that the protein phosphatase 2A (PP2A) regulatory subunit PPP2R2B is a crucial determinant of anti-HER2 response. PPP2R2B is downregulated in a substantial subset of HER2+ breast cancers, which correlates with poor clinical outcome and resistance to HER2-targeted therapies. EZH2-mediated histone modification accounts for the PPP2R2B downregulation, resulting in sustained phosphorylation of PP2A targets p70S6K and 4EBP1 which leads to resistance to inhibition by anti-HER2 treatments. Genetic depletion or inhibition of EZH2 by a clinically-available EZH2 inhibitor restores PPP2R2B expression, abolishes the residual phosphorylation of p70S6K and 4EBP1, and resensitizes HER2+ breast cancer cells to anti-HER2 treatments both in vitro and in vivo. Furthermore, the same epigenetic mechanism also contributes to the development of acquired resistance through clonal selection. These findings identify EZH2-dependent PPP2R2B suppression as an epigenetic control of anti-HER2 resistance, potentially providing an opportuni...Continue Reading

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Citations

Sep 25, 2021·EMBO Reports·David Maria HollensteinWolfgang Reiter
Oct 9, 2021·Advanced Science·Fan ChenChristine F Brainson

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Datasets Mentioned

BETA
GSE62327

Methods Mentioned

BETA
phosphatase assay
ChIP
immunoprecipitation
xenograft
xenografts
PCR
Protein Assay
electrophoresis
flow cytometry
transfection

Clinical Trials Mentioned

NCT01309607

Software Mentioned

ImageJ
CompuSyn
ROC Plotter
JetSet
GraphPad Prism
KM Plotter
Plotter
KM
GOBO

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