title: 3'UTR shortening and EGF signaling: implications for breast cancer.
abstract: Alternative polyadenylation (APA) plays a role in gene expression regulation generally by shortening of 3'UTRs (untranslated regions) upon proliferative signals and relieving microRNA-mediated repression. Owing to high proliferative indices of triple negative breast cancers (TNBCs), we hypothesized APA to cause 3'UTR length changes in this aggressive subgroup of breast cancers. Our probe-based meta-analysis approach identified 3'UTR length alterations where the significant majority was shortening events (∼70%, 113 of 165) of mostly proliferation-related transcripts in 520 TNBC patients compared with controls. Representative shortening events were further investigated for their microRNA binding potentials by computational predictions and dual-luciferase assay. In silico-predicted 3'UTR shortening events were experimentally confirmed in patient and cell line samples. To begin addressing the underlying mechanisms, we found CSTF2 (cleavage stimulation factor 2), a major regulator of 3'UTR shortening to be up-regulated in response to epidermal growth factor (EGF). EGF treatment also resulted with further shortening of the 3'UTRs. To investigate the contribution of CSTF2 and 3'UTR length alterations to the proliferative phenotype, we showed pharmacological inhibition of the EGF pathway to lead to a reduction in CSTF2 levels. Accordingly, RNAi-induced silencing of CSTF2 decreased the proliferative rate of cancer cells. Therefore, our computational and experimental approach revealed a pattern of 3'UTR length changes in TNBC patients and a potential link between APA and EGF signaling. Overall, detection of 3'UTR length alterations of various genes may help the discovery of new cancer-related genes, which may have been overlooked in conventional microarray gene expression analyses.
authors.affiliation: Department of Biological Sciences and.
authors.forename: Hesna Begum
authors.initials: HB
authors.lastname: Akman
authors.affiliation: Department of Biological Sciences and.
authors.forename: Merve
authors.initials: M
authors.lastname: Oyken
authors.affiliation: Department of Biological Sciences and.
authors.forename: Taner
authors.initials: T
authors.lastname: Tuncer
authors.affiliation: Department of Computer Engineering, M.E.T.U., Ankara 06800, Turkey.
authors.forename: Tolga
authors.initials: T
authors.lastname: Can
authors.affiliation: Department of Biological Sciences and erson@metu.edu.tr.
authors.forename: Ayse Elif
authors.initials: AE
authors.lastname: Erson-Bensan
mesh_terms: D020413:3' Untranslated Regions; D045744:Cell Line, Tumor; D039241:Cleavage Stimulation Factor; D018572:Disease-Free Survival; D004815:Epidermal Growth Factor; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D026723:Polyadenylation; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C474466:CSTF2T protein, human; D039241:Cleavage Stimulation Factor; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D004815:Epidermal Growth Factor