Abstract 144: Genome-wide DNA methylation changes in AI-resistant breast cancer models during E2-treatment

Autor: Heather E. Cunliffe, Balkees Abderrahman, Stefan Winter, V. Craig Jordan, Siarhei Kandabarau, Hiltrud Brauch, Reiner Hoppe, Werner Schroth, Ping Fan
Rok vydání: 2020
Předmět:
Zdroj: Cancer Research. 80:144-144
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2020-144
Popis: Disruption of estrogen signaling with tamoxifen or aromatase inhibitors (AI) is the clinical standard for the treatment of estrogen receptor-positive breast cancer, yet resistance to antiestrogen therapies is inevitable. The long-term E2-deprived breast cancer models MCF-7:5C and MCF-7:2A mimic AI resistance and moreover are vulnerable to E2-induced apoptosis due to the reconfiguration of their survival signaling. E2-induced apoptosis which results from the accumulation of endoplasmic reticulum (ER), oxidative, and inflammatory stresses, is a new paradigm to subvert endocrine resistance, with sensors of the unfolded protein response (UPR) being important mediators of ER stress (Ariazi et al. 2011; Fan et al. 2013, 2015). Here we asked whether epigenetic modifications may play a role in this and investigated genome-wide changes of 5C and 2A DNA methylation patterns that occurred during E2 stimulation during a 72h time course with WS8 cells as a reference. Methylation patterns were established using the Illumina Infinium HumanMethylation450 BeadChip (Service XS, Leiden, NL), and raw intensities were normalized and filtered using the bioconductor minfi package. A linear model (bioconductor limma package) has been built to detect differentially methylated CpGs. F-statistics were calculated by empirical Bayes moderation of standard errors with "trend" and "robust" set “on”. We also performed whole-genome bisulfite sequencing (WGBS) in untreated cells using the Illumina HiSeq platform (GATC Biotech, Konstanz, DE) to obtain maximum baseline CpG coverage. Trimmed WGBS reads were aligned to the hg38 genome (Bismarck, PMC3102221), duplicates removed, and methylation levels extracted with MethylDackel (https://github.com/dpryan79/MethylDackel) with a 3x coverage threshold (Wreczycka et al. 2017). Raw methylation levels were smoothed and differential methylation called using the bsseq package (Hansen et al. 2012). At baseline, WGBS-derived profiles showed a 2-fold higher degree of hypomethylation (beta Citation Format: Reiner Hoppe, Siarhei Kandabarau, Ping Fan, Stefan Winter, Balkees Abderrahman, Heather Cunliffe, Werner Schroth, V. Craig Jordan, Hiltrud B. Brauch. Genome-wide DNA methylation changes in AI-resistant breast cancer models during E2-treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 144.
Databáze: OpenAIRE
Externí odkaz: