Alternative polyadenylation dependent 3'-UTR changes in triple negative breast cancers

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Tezin Türü: Doktora

Tezin Yürütüldüğü Kurum: Orta Doğu Teknik Üniversitesi, Fen Edebiyat Fakültesi, Biyolojik Bilimler Bölümü, Türkiye

Tezin Onay Tarihi: 2015

Öğrenci: TANER TUNCER

Eş Danışman: TOLGA CAN, AYŞE ELİF ERSON BENSAN

Özet:

Alternative polyadenylation (APA) may cause mRNA 3’-UTR (untranslated region) length changes in different physiological conditions and/or disease states. About half of mammalian genes use alternative polyadenylation to generate multiple mRNA isoforms differing in their 3′-UTRs. APA has been attracting attention due to roles in gene expression regulation by shortening or lengthening of 3'-UTRs upon proliferative signals. Triple Negative Breast Cancers (TNBCs) are aggressive subtypes of breast cancers with poor prognosis and high proliferation abilities. While microarray gene expression analyses provided vital information on breast cancer subtypes, conventional quantification of microarrays underestimate potential isoforms generated by alternative splicing and APA. Due to high proliferative indices; we hypothesized APA to play a role in TNBCs. We developed and used a probe based meta-analysis tool (APADetect). APADetect uses poly(A) site positions to group Affymetrix probes as proximal and distal sets. Here, 3-'UTR shortening or lengthening events were detected using APADetect in 520 TNBC and 82 normal breast samples. When compared to normal breast tissue, TNBC patients had significantly different APA patterns. In TNBCs, 68.5% of APA events (113 of 165) were 3'-UTR shortening and 31.5% (52 of 165) were 3'-UTR lengthening. Transcripts going through APA were mostly related to metabolic and transcriptional processes, consistent with a high proliferative state. Significantly altered 3’-UTR lengths in TNBCs were then correlated with patient characteristics, and compared to ER+ patients. Significantly shortened mRNAs were predicted to harbor fewer microRNA binding sites compared to their longer versions. Such 3’-UTR shortening events correlated with relapse free survival times of TNBC patients. Expression analysis confirmed the in silico results and showed increased shorter isoform generation for USP9X, and YME1L1. Our results, for the first time, show a potential role of APA in TNBCs. APA pattern changes and generation of different 3’ UTR isoforms may help us improve our understanding of TNBCs by discovering new cancer related genes which may have been overlooked in conventional microarray gene expression analyses