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Abstract
Estrogen hormones are implicated in a majority of breast cancers and estrogen receptor alpha (ER), the main nuclear factor mediating estrogen signaling, orchestrates a complex molecular circuitry that is not yet fully elucidated. Here, we investigated genome-wide DNA methylation, histone acetylation and transcription after estradiol (E2) deprivation and re-stimulation to better characterize the ability of ER to coordinate gene regulation. We found that E2 deprivation mostly resulted in DNA hypermethylation and histone deacetylation in enhancers. Transcriptome analysis revealed that E2 deprivation leads to a global down-regulation in gene expression, and more specifically of TET2 demethylase that may be involved in the DNA hypermethylation following short-term E2 deprivation. Further enrichment analysis of transcription factor (TF) binding and motif occurrence highlights the importance of ER connection mainly with two partner TF families, AP-1 and FOX. These interactions take place in the proximity of E2 deprivation-mediated differentially methylated and histone acetylated enhancers. Finally, while most deprivation-dependent epigenetic changes were reversed following E2 re-stimulation, DNA hypermethylation and H3K27 deacetylation at certain enhancers were partially retained. Overall, these results show that inactivation of ER mediates rapid and mostly reversible epigenetic changes at enhancers, and bring new insight into early events, which may ultimately lead to endocrine resistance.
Highlights
Despite the continuous efforts for prevention and surveillance, breast cancer (BC) remains the most common cancer in women across the world [1]
We found that prolonged E2 deprivation and re-stimulation result in time dependent changes in DNA methylation (DNAm) and histone modifications across diverse genomic regions, many of which occur within enhancer elements
While studies have shown that hypermethylation of enhancers may be a long-term consequence of reduced estrogen receptor (ER) activity, our study reveals that gain of methylation at enhancers occurs shortly following ER downregulation and that this hypermethylation increases in time
Summary
Despite the continuous efforts for prevention and surveillance, breast cancer (BC) remains the most common cancer in women across the world [1]. Steroid hormones, notably estrogens, have been recognized as key players in BC, and current chemopreventive strategies target hormonally responsive breast tumours. BCs are classified into different molecular subtypes mainly according to the presence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2), and their expression tends to determine the treatment approach. While on average only 7% of normal mammary epithelial cells express ER, more than 70% of breast tumours are ER-positive (ER+) which suggests that ER+ cells are more prone to oncogenesis, presumably due to their ability to respond to a variety of biological (endogenous estrogens) and environmental stimuli (such as steroidlike molecules) [2,3]. Treatment of ER+ BC patients is based on this characteristic as it lends itself readily to anti-estrogen therapy that down-regulates ER signalling and inhibits ER-induced cell proliferation.
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