Epigenome-wide SRC-1–Mediated Gene Silencing Represses Cellular Differentiation in Advanced Breast Cancer

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 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 metastatic tumors. 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 ( = 669) demonstrated that low expression of this prodifferentiation gene set significantly associated with poor clinical outcome ( = 0.00009). We demonstrate that the reactivation of these genes and reverses the aggressive phenotype. 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. .

The Impact of CRISPR-Cas9 on Age-related Disorders: From Pathology to Therapy

“…Overexpression of Src-1 resulted in hypermethylation induced downregulation of five target genes NTRK2, NR2F2, CTDP1, SETBP1 and POU3F2 [168]. In cell lines, the downregulation of these genes conferred an increased ability for self-renewal and invasive-metastatic features [168].…”

“…Overexpression of Src-1 resulted in hypermethylation induced downregulation of five target genes NTRK2, NR2F2, CTDP1, SETBP1 and POU3F2 [168]. In cell lines, the downregulation of these genes conferred an increased ability for self-renewal and invasive-metastatic features [168]. When Src-1 knock-out by CRISPR-Cas9 or demethylation treatment was performed, the target genes were instead up-regulated, and the cell lines showed a reduced capacity for self-renewal, colony formation, and a renewed sensitivity to the endocrine treatment [168].…”

“…In cell lines, the downregulation of these genes conferred an increased ability for self-renewal and invasive-metastatic features [168]. When Src-1 knock-out by CRISPR-Cas9 or demethylation treatment was performed, the target genes were instead up-regulated, and the cell lines showed a reduced capacity for self-renewal, colony formation, and a renewed sensitivity to the endocrine treatment [168]. When treating ER positive breast cancers, ER is frequently targeted in hormone therapy, although cancers may retain expression of ER while simultaneously developing resistance to the hormone therapy [169].…”

“…The silencing of CDK7 induced apoptosis and impaired cell growth, in addition to downregulating several embryonic transcription factors such as EGFR or Sox2 [ 167 ]. Epigenetic modifications play a critical role in the regulation of transcription [ 168 ]. Recently, the ER-regulator gene, Src-1, was found to cause aberrant methylation of genes involved in cellular differentiation and development, in both patient tumors and endocrine-resistant models of breast cancer cells, directly suppressing the genes [ 168 ].…”

Medulloblastoma: Challenges and advances in treatment and research

“…When H3K27me3 is erased by KDM gene family proteins, chromatin remodelers are recruited to H3K4me marks to promote differentiation. The biological repercussions of such mutations is an inappropriate silencing of pro‐differentiation genes—keeping cells in a poorly differentiated state typically indicative of aggressive tumors . Other epigenetic modifiers can also be mutated, and a list of these can be found in the following references …”