Type

Journal Article

Authors

Leonie S Young
Arnold D Hill
Andrew H Sims
Phillip J O'Halloran
Darran O'Connor
Sudipto Das
Lance Hudson
Siobhan P Purcell
Sinéad Cocchiglia
Nicola S Cosgrove
and 5 others

Subjects

Biochemistry

Topics
gene silencing breast cancer patients disease progression breast cancer drug resistance dna methylation estrogen receptor cancer cell

Epigenome-wide SRC-1 mediated gene silencing represses cellular differentiation in advanced breast cancer. (2017)

Abstract 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. Genome-wide multi-omics sequencing approach identified a differentially methylated hub of pro-differentiation 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 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 hyper-methylation 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 pro-differentiation gene set significantly associated with poor clinical outcome (p=0.00009). We demonstrate that the re-activation of these genes 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.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Leonie S Young, Arnold D Hill, Andrew H Sims, Phillip J O'Halloran, Darran O'Connor, Sudipto Das, Lance Hudson, Siobhan P Purcell, Sinéad Cocchiglia, Nicola S Cosgrove and 5 others

Experts in our system

1
Leonie S Young
Royal College of Surgeons in Ireland
Total Publications: 42
 
2
Arnold D K Hill
Royal College of Surgeons in Ireland
Total Publications: 110
 
3
Darran P O'Connor
Royal College of Surgeons in Ireland
Total Publications: 43
 
4
Sudipto Das
Royal College of Surgeons in Ireland
Total Publications: 15
 
5
Lance Hudson
Royal College of Surgeons in Ireland
Total Publications: 11
 
6
Sinéad Cocchiglia
Royal College of Surgeons in Ireland
Total Publications: 10