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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., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Impact of mRNA processing and/or modifications has long been associated with gene expression regulation. Accumulating evidence shows alternative polyadenylation (APA), as an mRNA related process, to emerge as a widespread mechanism in gene expression regulation. Through selecting alternate (proximal or distal) polyadenylation signals on the 3'-UTR of pre-mRNAs, APA generates multiple transcript isoforms which may even create proteomic diversity. Depending on the use of proximal or distal polyadenylation sites, 3'-UTR lengths can vary in a tightly controlled manner in a spatial and temporal mode. Therefore, APA and its deregulation with potential consequences are highly relevant to normal and disease states. In this review, in light of recent findings in the literature, mechanism and types of APA and roles of APA in biological processes (i.e. proliferation, development, differentiation, and transformation) are discussed.