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The impact of Fulvestrant on Estrogen Receptor-Driven Chromatin Dynamics in Breast Cancer Cells [RNA-seq]

ABSTRACT: Background: Epigenetic dysregulations are linked to various diseases, including cancer. Among them, breast cancer is the second leading cause of cancer-related deaths in women with 50% of mortalities attributable to estrogen receptor-positive (ER+) tumors. Endocrine therapies targeting the ER such as Tamoxifen, Fulvestrant (FULV) and Aromatase inhibitors, are widely used in the clinic. Among these therapeutic agents, FULV has been shown to fully antagonize ER activity, primarily through the rapid degradation and elimination of ER from target tissues. However, recent findings indicate that ER, when engaged with FULV, retains the ability to translocate to the nucleus and bind DNA whereas appearing transcriptionally inert. Results: In this study, we aimed to further investigate the effects of FULV and Estradiol (E2), the natural ER ligand, on ER cistrome, chromatin accessibility, gene transcription, and H3K27ac genome-wide patterns in ER+ breast cancer cell lines. Using the innovative CUT&Tag technology, we first confirmed that both FULV and E2 promote ER binding to DNA. Our findings revealed that E2 not only enhances chromatin accessibility and gene expression but also increases H3K27ac levels at ER binding sites. In contrast, FULV does not significantly alter chromatin accessibility or transcription but is not completely inert, as it induces increases in H3K27ac at a subset of ER binding sites. These observations indicate a decoupling between histone acetylation and transcriptional output under FULV treatment. Conclusions: This study provides new insights into the mechanistic impact of FULV on ER activity, highlighting its ability to modulate H3K27ac dynamics even in the absence of transcriptional changes. These findings underscore the complexity of ER signaling and suggest that FULV’s therapeutic effects may extend beyond simple antagonism of ER activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310291 | GEO | 2026/05/25

REPOSITORIES: GEO

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Project description:The interplay between mitogenic and proinflammatory signaling pathways play key roles in determining the phenotypes and clinical outcomes of breast cancers. We have used global nuclear run-on coupled with deep sequencing to characterize the immediate transcriptional responses of MCF-7 breast cancer cells treated with estradiol, TNF?, or both. In addition, we have integrated these data with chromatin immunoprecipitation coupled with deep sequencing for estrogen receptor alpha (ER?), the pioneer factor FoxA1 and the p65 subunit of the NF-?B transcription factor. Our results indicate extensive transcriptional interplay between these two signaling pathways, which is observed for a number of classical mitogenic and proinflammatory protein-coding genes. In addition, GRO-seq has allowed us to capture the transcriptional crosstalk at the genomic locations encoding for long non-coding RNAs, a poorly characterized class of RNAs which have been shown to play important roles in cancer outcomes. The synergistic and antagonistic interplay between estrogen and TNF? signaling at the gene level is also evident in the patterns of ER? and NF-?B binding, which relocalize to new binding sites that are not occupied by either treatment alone. Interestingly, the chromatin accessibility of classical ER? binding sites is predetermined prior to estrogen treatment, whereas ER? binding sites gained upon co-treatment with TNF? require NF-?B and FoxA1 to promote chromatin accessibility de novo. Our data suggest that TNF? signaling recruits FoxA1 and NF-?B to latent ER? enhancer locations and directly impact ER? enhancer accessibility. Binding of ER? to latent enhancers upon co-treatment, results in increased enhancer transcription, target gene expression and altered cellular response. This provides a mechanistic framework for understanding the molecular basis for integration of mitogenic and proinflammatory signaling in breast cancer. Using GRO-seq and ChIP-seq (ER, FoxA1 and p65) to assay the molecular crosstalk of MCF-7 cells treated with E2, TNFa or both E2+TNFa.

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The impact of Fulvestrant on Estrogen Receptor-Driven Chromatin Dynamics in Breast Cancer Cells [RNA-seq]

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