3’UTR alterations in connection with estrogen receptor-alpha in breast cancer

Thesis Type: Postgraduate

Institution Of The Thesis: Orta Doğu Teknik Üniversitesi, Faculty of Arts and Sciences, Department of Biology, Turkey

Approval Date: 2014




Alternative polyadenylation (APA) generates transcript isoforms with different 3’UTR (untranslated region) lengths due to the position of poly(A) tail. This difference may alter the stability and location of mRNA isoforms in cell. APA has been observed in various cellular states. For example, preferential use of distal poly(A) sites and 3’UTR lengthening occurs during development. However, in proliferation, use of poly(A) sites result with 3’UTR shortening for a large group of genes. In cancer cells, APA seems to be deregulated based on few observations. Widespread 3’UTR shortening was reported in vaious cancers. For example, our group revealed 3’UTR shortening of CDC6 induced by estrogen in breast cancer cells. In this study, we aim to investigate the 3’UTR alterations in estrogen receptor (ER)-positive breast cancer patients and cell models. For this purpose, publicly available microarray datasets were analyzed by a probe-based microarray analysis tool (APADetect). Based on the means of proximal to distal poly(A) site ratios of individual transcripts, the SLR (short-long ratio) was calculated as an indication of short vs. long 3’UTR abundance. Significance Analysis of Microarrays (SAM) determined significant genes that had 3’UTR shortened or lengthened genes. These genes were further analyzed in silico to reveal 3’UTR alterations in ER(+) breast cancer patients compared to normal breast samples. Interestingly, we did not detect APA based changes in patients in connection with relapse information. Further studies of APA in an ERα transfected MDA-MB-231 cell line model revealed a complicated picture of APA possibly as a consequence of direct and indirect effects of ERα. Our results suggest involvement of APA mechanisms in ERα action mechanisms. Possible link between ERα regulated transcription and APA remains to be elucidated.