The impact of Fulvestrant on Estrogen Receptor-Driven Chromatin Dynamics in breast cancer cells points to a disconnect between chromatin opening and histone acetylation [CUT&Tag]

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 Estrogen Receptor (ER) such as Tamoxifen, Fulvestrant and Aromatase inhibitors, are widely used in the clinic. Among these therapeutic agents, Fulvestrant 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 Fulvestrant, 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 Fulvestrant and Estradiol, an ER natural ligand, on ER cistrome, chromatin accessibility, and H3K27ac genome-wide patterns in an ER+ breast cancer cell line. Using the innovative CUT&Tag technology, we first confirmed that both Fulvestrant and Estradiol promote ER binding to DNA. Our findings revealed that Estradiol not only enhances chromatin accessibility but also increases H3K27ac levels at ER binding sites. In contrast, while Fulvestrant does not significantly alter chromatin accessibility, it can induce increases in H3K27ac levels at a subset of ER binding sites. Our observations suggest that Fulvestrant may modulate breast cancer transcriptional landscape by impacting H3K27ac dynamics, even in the absence of changes in chromatin accessibility. Conclusions: This study provides new insights on the mechanistic impact of Fulvestrant on Estrogen Receptor activity and their potential implications on target gene expression, particularly highlighting a novel putative role of H3K27ac dynamics in these processes.