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

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.