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 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 ex vivo metastatic tumours. 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 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 in vitro and ex vivo reverses the aggressive phenotype. Conclusion: 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.
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