American Association for Cancer Research
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Supplementary Table from Epigenome-wide SRC-1–Mediated Gene Silencing Represses Cellular Differentiation in Advanced Breast Cancer

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journal contribution
posted on 2023-03-31, 19:49 authored by Elspeth Ward, Damir Varešlija, Sara Charmsaz, Ailis Fagan, Alacoque L. Browne, Nicola Cosgrove, Sinéad Cocchiglia, Siobhan P. Purcell, Lance Hudson, Sudipto Das, Darran O'Connor, Philip J. O'Halloran, Andrew H. Sims, Arnold D. Hill, Leonie S. Young

Table S2: 251 genes within 5kb of SRC-1 peak upstream of the TSS (Ensembl ID)


Breast Cancer Research Foundation

Science Foundation Ireland



Purpose: Despite the clinical utility of endocrine therapies for estrogen receptor–positive (ER) breast cancer, up to 40% of patients eventually develop resistance, leading to disease progression. The molecular determinants that drive this adaptation to treatment remain poorly understood. Methylome aberrations drive cancer growth yet the functional role and mechanism of these epimutations in drug resistance are poorly elucidated.Experimental Design: Genome-wide multi-omics sequencing approach identified a differentially methylated hub of prodifferentiation genes in endocrine resistant breast cancer patients and cell models. Clinical relevance of the functionally validated methyl-targets was assessed in a cohort of endocrine-treated human breast cancers and patient-derived ex vivo metastatic tumors.Results: Enhanced global hypermethylation was observed in endocrine treatment resistant cells and patient metastasis relative to sensitive parent cells and matched primary breast tumor, respectively. Using paired methylation and transcriptional profiles, we found that SRC-1–dependent alterations in endocrine resistance lead to aberrant hypermethylation that resulted in reduced expression of a set of differentiation genes. Analysis of ER-positive endocrine-treated human breast tumors (n = 669) demonstrated that low expression of this prodifferentiation gene set significantly associated with poor clinical outcome (P = 0.00009). We demonstrate that the reactivation of these genes in vitro and ex vivo reverses the aggressive phenotype.Conclusions: Our work demonstrates that SRC-1-dependent epigenetic remodeling is a ’high level’ regulator of the poorly differentiated state in ER-positive breast cancer. Collectively these data revealed an epigenetic reprograming pathway, whereby concerted differential DNA methylation is potentiated by SRC-1 in the endocrine resistant setting. Clin Cancer Res; 24(15); 3692–703. ©2018 AACR.