Oncotarget

Research Papers:

Depletion of eIF2·GTP·Met-tRNAi translation initiation complex up-regulates BRCA1 expression in vitro and in vivo

Bertal H. Aktas _, Paula Bordelois, Selen Peker, Sophia Merajver and Jose A. Halperin

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Oncotarget. 2015; 6:6902-6914. https://doi.org/10.18632/oncotarget.3125

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Abstract

Bertal H. Aktas1,2,*, Paula Bordelois2,*, Selen Peker1,3, Sophia Merajver4, Jose A. Halperin1,2

1Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA

2Harvard Medical School, Boston, MA, USA

3Ankara University Biotechnology Institute, Ankara, Turkey

4Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

*These authors have contributed equally to this work

Correspondence to:

Jose A. Halperin, e-mail: Jose_halperin@hms.harvard.edu

Keywords: BRCA1, EPA, Fish Oil, eIF2·GTP·Met-tRNAi, uORF

Received: November 04, 2014     Accepted: January 09, 2015     Published: February 07, 2015

ABSTRACT

Most sporadic breast and ovarian cancers express low levels of the breast cancer susceptibility gene, BRCA1. The BRCA1 gene produces two transcripts, mRNAa and mRNAb. mRNAb, present in breast cancer but not in normal mammary epithelial cells, contains three upstream open reading frames (uORFs) in its 5’UTR and is translationally repressed. Comparable tandem uORFs are characteristically seen in mRNAs whose translational efficiency paradoxically increases when the overall translation rate is decreased due to phosphorylation of eukaryotic translation initiation factor 2 α (eIF2α). Here we show fish oil derived eicosopanthenoic acid (EPA) that induces eIF2α phosphorylation translationally up-regulates the expression of BRCA1 in human breast cancer cells. We demonstrate further that a diet rich in EPA strongly induces expression of BRCA1 in human breast cancer xenografts.


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