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Conference Paper: Translational regulation by eIF4E and its contribution to tamoxifen resistance in breast cancer

TitleTranslational regulation by eIF4E and its contribution to tamoxifen resistance in breast cancer
Authors
Issue Date2016
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
The 2016 Annual Meeting of the American Association for Cancer Research (AACR 2016), New Orleans, LA., 16-20 April 2016. In Cancer Research, 2016, v. 76 n. 14 suppl., abstract no. 4761 How to Cite?
AbstractBreast cancer is one of the prevalent causes of cancer in women and its occurrence has been rising in the last few decades. Two thirds of breast cancer patients are ER-positive and can receive tamoxifen (TAM) treatment. Unfortunately, many of the patients eventually develop resistance to tamoxifen. Identifying a molecular marker associated with tamoxifen resistance would help in designing better therapeutic strategies to overcome this. In eukaryotes, translation initiation is the most regulated step. Abnormal translation machinery underlies a variety of human diseases including cancers. Eukaryotic translation initiation factor 4E (eIF4E) is the least abundant initiation factor and is believed to be the rate limiting step for translation initiation. Overexpression of eIF4E in cells selectively promotes translation of mRNAs involved in cell proliferation, apoptosis and tumor progression. Recently, eIF4E overexpression has been implicated in drug resistance in melanoma1. We hypothesized that eIF4E may also be involved in tamoxifen resistance. The aim of this study was to characterize the role of eIF4E in tamoxifen resistance and identify novel molecular targets that may be translationally regulated. Immunohistochemistry (IHC) staining of eIF4E showed up-regulation in human breast cancer samples compared with non-tumor counterparts. In silico analysis predicted that ERá and FOXM1 have a long and highly structured 5’-UTR, which are sensitive to the expression level of eIF4E. Polysomal fractionation confirmed that ERá and FOXM1 mRNA were more actively translated in MCF7 than in MCF10A. The correlation between eIF4E and ERá/FOXM1 were further confirmed in tissue microarray (TMA). The role of eIF4E in conferring TAM resistance was studied by MTT assays. Overexpression of eIF4E induced TAM resistance while knockdown eIF4E sensitized cells to TAM. Additionally, overexpression of eIF4E upregulated ERá/FOXM1 expression at protein level while knockdown eIF4E downregulated their expression at protein level. Our results show that eIF4E induced TAM resistance possibly through translational regulation of ERá/FOXM1. eIF4E is a promising biomarker for anti-estrogen drug responsiveness and a future therapeutic target for treating drug resistant breast cancer patients. REFERENCE: 1. Zhan Y, et al. The role of eIF4E in response and acquired resistance to vemurafenib in melanoma J Invest Dermatol. 2015 May;135(5):1368-76.
DescriptionThis journal suppl. entitled: Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA
Session - Experimental and Molecular Therapeutics: abstract no. 4761
Persistent Identifierhttp://hdl.handle.net/10722/235175
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372

 

DC FieldValueLanguage
dc.contributor.authorGong, C-
dc.contributor.authorMok, KC-
dc.contributor.authorCheung, YN-
dc.contributor.authorMan, PS-
dc.contributor.authorLam, EWF-
dc.contributor.authorKhoo, US-
dc.date.accessioned2016-10-14T13:51:43Z-
dc.date.available2016-10-14T13:51:43Z-
dc.date.issued2016-
dc.identifier.citationThe 2016 Annual Meeting of the American Association for Cancer Research (AACR 2016), New Orleans, LA., 16-20 April 2016. In Cancer Research, 2016, v. 76 n. 14 suppl., abstract no. 4761-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/235175-
dc.descriptionThis journal suppl. entitled: Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA-
dc.descriptionSession - Experimental and Molecular Therapeutics: abstract no. 4761-
dc.description.abstractBreast cancer is one of the prevalent causes of cancer in women and its occurrence has been rising in the last few decades. Two thirds of breast cancer patients are ER-positive and can receive tamoxifen (TAM) treatment. Unfortunately, many of the patients eventually develop resistance to tamoxifen. Identifying a molecular marker associated with tamoxifen resistance would help in designing better therapeutic strategies to overcome this. In eukaryotes, translation initiation is the most regulated step. Abnormal translation machinery underlies a variety of human diseases including cancers. Eukaryotic translation initiation factor 4E (eIF4E) is the least abundant initiation factor and is believed to be the rate limiting step for translation initiation. Overexpression of eIF4E in cells selectively promotes translation of mRNAs involved in cell proliferation, apoptosis and tumor progression. Recently, eIF4E overexpression has been implicated in drug resistance in melanoma1. We hypothesized that eIF4E may also be involved in tamoxifen resistance. The aim of this study was to characterize the role of eIF4E in tamoxifen resistance and identify novel molecular targets that may be translationally regulated. Immunohistochemistry (IHC) staining of eIF4E showed up-regulation in human breast cancer samples compared with non-tumor counterparts. In silico analysis predicted that ERá and FOXM1 have a long and highly structured 5’-UTR, which are sensitive to the expression level of eIF4E. Polysomal fractionation confirmed that ERá and FOXM1 mRNA were more actively translated in MCF7 than in MCF10A. The correlation between eIF4E and ERá/FOXM1 were further confirmed in tissue microarray (TMA). The role of eIF4E in conferring TAM resistance was studied by MTT assays. Overexpression of eIF4E induced TAM resistance while knockdown eIF4E sensitized cells to TAM. Additionally, overexpression of eIF4E upregulated ERá/FOXM1 expression at protein level while knockdown eIF4E downregulated their expression at protein level. Our results show that eIF4E induced TAM resistance possibly through translational regulation of ERá/FOXM1. eIF4E is a promising biomarker for anti-estrogen drug responsiveness and a future therapeutic target for treating drug resistant breast cancer patients. REFERENCE: 1. Zhan Y, et al. The role of eIF4E in response and acquired resistance to vemurafenib in melanoma J Invest Dermatol. 2015 May;135(5):1368-76.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/-
dc.relation.ispartofCancer Research-
dc.titleTranslational regulation by eIF4E and its contribution to tamoxifen resistance in breast cancer-
dc.typeConference_Paper-
dc.identifier.emailCheung, YN: jennyync@hku.hk-
dc.identifier.emailMan, PS: ellenman@hku.hk-
dc.identifier.emailKhoo, US: uskhoo@hku.hk-
dc.identifier.authorityKhoo, US=rp00362-
dc.identifier.doi10.1158/1538-7445.AM2016-4761-
dc.identifier.hkuros268953-
dc.identifier.volume76-
dc.identifier.issue14 suppl.-
dc.publisher.placeUnited States-

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