SRC-1 Mediates DNA Methylation Driving a De-Differentiated State in Endocrine Resistant Breast Cancer by Recruiting a Methyl Regulatory Complex
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Breast cancer progression occurs through the accumulation of genetic and epigenetic abnormalities. Hormone receptor positive breast cancer is driven by the estrogen receptor whose expression is indicative of good prognosis. Despite the clinical utility of endocrine therapies for estrogen receptor positive 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 with genetic and epigenetic modifications implicated. Increasing evidence suggests that aberrant DNA hyper-methylation of tumour suppressors and hypo-methylation of oncogenes driving dysregulation of differentiation/developmental genes may represent a major mechanism underlying tumour progression. Methylome aberrations have been found to drive cancer growth yet the functional role and mechanism of these epi-mutations in drug resistance are poorly elucidated.
In this study enhanced global hyper-methylation in endocrine resistant cell models and patient metastasis relative to sensitive parent cells and matched primary breast tumour respectively was observed. A multi-omic sequencing approach combining methylome analysis and transcriptional profiling was utilised. This demonstrated that SRC-1, contrary to its classic role as an estrogen receptor coactivator is essential for epigenetic remodelling of key pro-differentiation genes. This pro-differentiation gene set was shown in vitro to have several tumour suppressor gene characteristics, whose repression aids de-differentiated aggressive disease phenotype. SRC-1 was shown to regulate the methylation status of this pro-differentiation gene set by recruiting a methyl complex including MBD2, MeCP2 and HDAC2. Analysis of human breast tumours demonstrated that low expression of this pro-differentiation gene set significantly associated with poor clinical outcome in tamoxifen treated population and that the re-activation of these genes in vitro and ex vivo reverses the aggressive phenotype.
This work demonstrates that SRC-1 via epigenetic remodelling mechanics is a ‘high level’ regulator of the poorly differentiated state in estrogen receptor positive xiii 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.