Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming Journal Article

Authors: Geter, P. A.; Ernlund, A. W.; Bakogianni, S.; Alard, A.; Arju, R.; Giashuddin, S.; Gadi, A.; Bromberg, J.; Schneider, R. J.
Article Title: Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming
Abstract: The majority of breast cancers expresses the estrogen receptor (ER+) and is treated with anti-estrogen therapies, particularly tamoxifen in premenopausal women. However, tamoxifen resistance is responsible for a large proportion of breast cancer deaths. Using small molecule inhibitors, phospho-mimetic proteins, tamoxifen-sensitive and tamoxifen-resistant breast cancer cells, a tamoxifen-resistant patient-derived xenograft model, patient tumor tissues, and genome-wide transcription and translation studies, we show that tamoxifen resistance involves selective mRNA translational reprogramming to an anti-estrogen state by Runx2 and other mRNAs. Tamoxifen-resistant translational reprogramming is shown to be mediated by increased expression of eIF4E and its increased availability by hyperactivemTOR and to require phosphorylation of eIF4E at Ser209 by increasedMNKactivity. Resensitization to tamoxifen is restored only by reducing eIF4E expression or mTOR activity and also blocking MNK1 phosphorylation of eIF4E. mRNAs specifically translationally up-regulated with tamoxifen resistance include Runx2, which inhibits ER signaling and estrogen responses and promotes breast cancer metastasis. Silencing Runx2 significantly restores tamoxifen sensitivity. Tamoxifen-resistant but not tamoxifen-sensitive patient ER+ breast cancer specimens also demonstrate strongly increased MNK phosphorylation of eIF4E. eIF4E levels, availability, and phosphorylation therefore promote tamoxifen resistance in ER+ breast cancer through selective mRNA translational reprogramming. © 2017 Geter et al.
Keywords: adult; protein expression; unclassified drug; human cell; cancer combination chemotherapy; antineoplastic agent; cancer diagnosis; translation initiation; cell proliferation; cell survival; cell growth; genome-wide association study; tumor xenograft; enzyme activity; cancer resistance; enzyme phosphorylation; messenger rna; mammalian target of rapamycin; initiation factor 4e; mitogen activated protein kinase 1; rna translation; tamoxifen; down regulation; upregulation; gene silencing; everolimus; antiestrogen; nuclear reprogramming; eif4e; cap-dependent translation; translational control; transcription factor runx2; estrogen receptor positive breast cancer; human; female; priority journal; article; mcf-7 cell line; er+ breast cancer; cgp 57380; hek293-ft cell line
Journal Title: Genes and Development
Volume: 31
Issue: 22
ISSN: 0890-9369
Publisher: Cold Spring Harbor Laboratory Press  
Date Published: 2017-11-15
Start Page: 2235
End Page: 2249
Language: English
DOI: 10.1101/gad.305631.117
PROVIDER: scopus
PMCID: PMC5769768
PUBMED: 29269484
Notes: Article -- Export Date: 1 February 2018 -- Source: Scopus
Citation Impact
MSK Authors
  1. Jacqueline Bromberg
    121 Bromberg