APA isoform diversity in triple negative breast cancers

Date

2017-04-05

Author

AKMAN TUNCER, HESNA BEGÜM
ÖYKEN, MERVE
AĞUŞ, HIZLAN HINCAL
Erdem, Murat
Çiçek, Esra
Can, Tolga
Erson Bensan, Ayşe Elif

Metadata

Show full item record

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Item Usage Stats

124
views

0
downloads

Alternative polyadenylation (APA) plays a role in gene expression regulation generally by shortening of 3'UTRs 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 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 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 3'UTRs. Accordingly, RNAi-induced silencing of CSTF2 decreased the proliferative rate of cancer cells. Therefore, our integrated approach revealed a pattern of 3'UTR 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.

Subject Keywords

Oncology

URI

https://hdl.handle.net/11511/34417

DOI

https://doi.org/10.1158/1538-7445.am2017-3374

Collections

Department of Biology, Conference / Seminar

Suggestions

OpenMETU
Core

RanBPM (RanBP9) regulates mouse c-Kit receptor level and is essential for normal development of bone marrow progenitor cells. Puverel, S; Kiriş, Erkan; Singh, S; Klarmann, KD; Coppola, V; Keller, JR; Tessarollo, L (Impact Journals, LLC, 2016-12-20) c-Kit is a tyrosine kinase receptor important for gametogenesis, hematopoiesis, melanogenesis and mast cell biology. Dysregulation of c-Kit function is oncogenic and its expression in the stem cell niche of a number of tissues has underlined its relevance for regenerative medicine and hematopoietic stem cell biology. Yet, very little is known about the mechanisms that control c-Kit protein levels. Here we show that the RanBPM/RanBP9 scaffold protein binds to c-Kit and is necessary for normal c-Kit protein e...
3 ' UTR shortening and EGF signaling: implications for breast cancer AKMAN, Hesna Begum; ÖYKEN, MERVE; TUNCER, Taner; Can, Tolga; Erson Bensan, Ayşe Elif (2015-12-15) 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 (si...
Investigation of a mechanistic link between 15-Lipoxygenase-1 (15-LOX-1) and Metastasis Associated Protein 1 (MTA1) in human colorectal carcinoma cell lines ÇAĞATAY, SİBEL; Banerjee, Sreeparna (2013-09-01) Background: Metastasis Associated Protein 1 (MTA1) is a member of the nuclear remodeling and histone deacetylase (NuRD) complex that is known to repress the expression of several tumor suppressor genes. 15-lipoxygenase-1 (15-LOX-1), a member of the inflammatory eicosanoid pathway, has been shown by us and others to have an anti-tumorigenic role in colon cancer. ALOX15 was recently shown to be repressed by the NuRD complex. Previously we have reported that ectopic expression of 15-LOX-1 in colon cancer cells...
Serum Glycan Signatures of Gastric Cancer Özcan Kabasakal, Süreyya; Ruhaak, L. Renee; Torres, Javier; Cooke, Cara L.; An, Hyun Joo; Hua, Serenus; Williams, Cynthia C.; Dimapasoc, Lauren M.; Kim, Jae Han; Camorlinga-Ponce, Margarita; Rocke, David; Lebrilla, Carlito B.; Solnick, Jay V. (American Association for Cancer Research (AACR), 2014-02-01) Glycomics, a comprehensive study of glycans expressed in biologic systems, is emerging as a simple yet highly sensitive diagnostic tool for disease onset and progression. This study aimed to use glycomics to investigate glycan markers that would differentiate patients with gastric cancer from those with nonatrophic gastritis. Patients with duodenal ulcer were also included because they are thought to represent a biologically different response to infection with Helicobacter pylori, a bacterial infection tha...
RNA-biology ruling cancer progression? Focus on 3 ' UTRs and splicing Erson Bensan, Ayşe Elif (Springer Science and Business Media LLC, 2020-09-01) The protein-coding regions of mRNAs have the information to make proteins and hence have been at the center of attention for understanding altered protein functions in disease states, including cancer. Indeed, the discovery of genomic alterations and driver mutations that change protein levels and/or activity has been pivotal in our understanding of cancer biology. However, to better understand complex molecular mechanisms that are deregulated in cancers, we also need to look at non-coding parts of mRNAs, i...

Citation Formats

H. B. AKMAN TUNCER et al., “APA isoform diversity in triple negative breast cancers,” 2017, vol. 77, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/34417.