title: Depletion of eIF2·GTP·Met-tRNAi translation initiation complex up-regulates BRCA1 expression in vitro and in vivo.
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.
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Bertal H
authors.initials: BH
authors.lastname: Aktas
authors.affiliation: Harvard Medical School, Boston, MA, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Bordelois
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA.|Ankara University Biotechnology Institute, Ankara, Turkey.
authors.forename: Selen
authors.initials: S
authors.lastname: Peker
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Merajver
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Halperin
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015118:Eicosapentaenoic Acid / Q000737:chemistry*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005260:Female; D005395:Fish Oils / Q000737:chemistry*; D006160:Guanosine Triphosphate / Q000737:chemistry*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016366:Open Reading Frames; D010766:Phosphorylation; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D012358:RNA, Transfer, Met / Q000737:chemistry*
chemical_list: D020121:5' Untranslated Regions; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D015852:Eukaryotic Initiation Factor-2; D005395:Fish Oils; D012333:RNA, Messenger; D012358:RNA, Transfer, Met; D006160:Guanosine Triphosphate; D015118:Eicosapentaenoic Acid
keywords: BRCA1; EPA; eIF2·GTP·Met-tRNAi; fish oil; uORF