Phosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer

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Title: Phosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer
Authors: Lam, E
Gong, C
Fujino, K
Item Type: Journal Article
Abstract: Eukaryotic translation initiation factor 4E (eIF4E) selectively promotes translation of mRNAs with atypically long and structured 5′-UTRs and has been implicated in drug resistance. Through genome-wide transcriptome and translatome analysis we revealed eIF4E overexpression could promote cellular activities mediated by ERα and FOXM1 signalling pathways. Whilst eIF4E overexpression could enhance the translation of both ERα and FOXM1, it also led to enhanced transcription of FOXM1. Polysome fractionation experiments confirmed eIF4E could modulate the translation of ERα and FOXM1 mRNA. The enhancement of FOXM1 transcription was contingent upon the presence of ERα, and it was the high levels of FOXM1 that conferred Tamoxifen resistance. Furthermore, tamoxifen resistance was conferred by phosphorylation independent eIF4E overexpression. Immunohistochemistry on 134 estrogen receptor (ER+) primary breast cancer samples confirmed that high eIF4E expression was significantly associated with increased ERα and FOXM1, and significantly associated with tamoxifen resistance. Our study uncovers a novel mechanism whereby phosphorylation independent eIF4E translational reprogramming in governing the protein synthesis of ERα and FOXM1 contributes to anti-estrogen insensitivity in ER+ breast cancer. In eIF4E overexpressing breast cancer, the increased ERα protein expression in turn enhances FOXM1 transcription, which together with its increased translation regulated by eIF4E, contributes to tamoxifen resistance. Coupled with eIF4E translational regulation, our study highlights an important mechanism conferring tamoxifen resistance via both ERα dependent and independent pathways.
Issue Date: 9-Apr-2020
Date of Acceptance: 5-Feb-2020
URI: http://hdl.handle.net/10044/1/77609
DOI: 10.1038/s41388-020-1210-y
ISSN: 0950-9232
Publisher: Springer Nature [academic journals on nature.com]
Start Page: 3206
End Page: 3217
Journal / Book Title: Oncogene
Volume: 39
Copyright Statement: © The Author(s) 2020. This article is published with open access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons. org/licenses/by/4.0/.
Sponsor/Funder: Cancer Research UK
Breast Cancer Care & Breast Cancer Now
Medical Research Council (MRC)
Breast Cancer Care & Breast Cancer Now
Funder's Grant Number: 12011
2012MayPR070
MR/N012097/1
2012NovemberPhD016
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
TRANSCRIPTION FACTOR
INITIATION-FACTORS
PROTEIN-SYNTHESIS
ER-ALPHA
THERAPY
EXPRESSION
FOXM1
SENSITIVITY
MECHANISMS
RECEPTOR
1103 Clinical Sciences
1112 Oncology and Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Online Publication Date: 2020-02-17
Appears in Collections:Department of Surgery and Cancer
Department of Surgery and Cancer