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

TitlePhosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer
Authors
KeywordsAK 47 cell line
breast cancer
breast cancer cell line
cancer resistance
controlled study
Issue Date2020
PublisherSpringer Nature [academic journals on nature.com]: Hybrid Journal. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2020, v. 39, p. 3206-3217 How to Cite?
AbstractEukaryotic 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.
Persistent Identifierhttp://hdl.handle.net/10722/287187
ISSN
2019 Impact Factor: 7.971
2015 SCImago Journal Rankings: 4.047
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorGong, C-
dc.contributor.authorTsoi, H-
dc.contributor.authorMok, KC-
dc.contributor.authorCheung, J-
dc.contributor.authorMan, EPS-
dc.contributor.authorFujino, K-
dc.contributor.authorWong, A-
dc.contributor.authorLam, EWF-
dc.contributor.authorKhoo, US-
dc.date.accessioned2020-09-22T02:57:08Z-
dc.date.available2020-09-22T02:57:08Z-
dc.date.issued2020-
dc.identifier.citationOncogene, 2020, v. 39, p. 3206-3217-
dc.identifier.issn0950-9232-
dc.identifier.urihttp://hdl.handle.net/10722/287187-
dc.description.abstractEukaryotic 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.-
dc.languageeng-
dc.publisherSpringer Nature [academic journals on nature.com]: Hybrid Journal. The Journal's web site is located at http://www.nature.com/onc-
dc.relation.ispartofOncogene-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectAK 47 cell line-
dc.subjectbreast cancer-
dc.subjectbreast cancer cell line-
dc.subjectcancer resistance-
dc.subjectcontrolled study-
dc.titlePhosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer-
dc.typeArticle-
dc.identifier.emailTsoi, H: tsoiho@hku.hk-
dc.identifier.emailMan, EPS: ellenman@hku.hk-
dc.identifier.emailKhoo, US: uskhoo@hku.hk-
dc.identifier.authorityKhoo, US=rp00362-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s41388-020-1210-y-
dc.identifier.pmid32066877-
dc.identifier.pmcidPMC7142019-
dc.identifier.scopuseid_2-s2.0-85079719153-
dc.identifier.hkuros314322-
dc.identifier.volume39-
dc.identifier.spage3206-
dc.identifier.epage3217-
dc.publisher.placeUnited Kingdom-

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