LAUSR

Alternative polyadenylation (APA) plays a role in gene expression regulation generally by shortening of 39UTRs and relieving microRNA-mediated repression. Therefore, APA is gaining increased attention as a potential mechanism to activate oncogenes. Owing to high proliferative indices of triple negative breast cancers (TNBCs), we hypothesized APA to cause 39UTR length changes in this aggressive subgroup of breast cancers. Our probe-based meta-analysis approach identified 39UTR length alterations where the significant majority was shortening events (70%, 113 of 165) of mostly proliferation-related transcripts in over 500 TNBC patients compared with normal breast tissue. Representative shortening events correlated with increased protein levels and relapse free survival of patients, suggesting functional significance of isoform variability. To begin addressing the underlying mechanisms of 3’UTR shortening, we turned to APA machinery proteins. We detected variable expression of APA machinery proteins in different breast cancer subtypes but CSTF2 (cleavage stimulation factor 2) has the most prominent overexpression in breast cancer cells. Therefore, among potential regulators of 3’UTR shortening, we further investigated the role of CSTF2 in proximal polyA signal selection. Because some of the TNBC patients are EGFR positive, we found EGF treatment to cause increased CSTF2 levels. Higher CSTF2 levels indeed correlated with further shortening of the 39UTRs. Accordingly, RNAi-induced silencing of CSTF2 decreased the proliferative rate of cancer cells. Therefore, our integrated approach revealed a pattern of 39UTR length changes in TNBC patients and a potential link between APA and EGF signaling. Further studies are underway to investigate the mechanistic link between EGF signaling and regulation of 3’UTR lengths. (This work is funded by TUBITAK 112S478 and 114Z884) Citation Format: Ayse Elif Erson-Bensan, Begum H. Akman, Merve Oyken, Hizlan H. Agus, Esra Yavuz, Murat Erdem, Tolga Can. APA isoform diversity in triple negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3374. doi:10.1158/1538-7445.AM2017-3374