The impact of fulvestrant on estrogen receptor-driven chromatin dynamics in breast cancer cells

Epigenetic dysregulations are linked to several 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. FULV has been shown to fully antagonize ER activity mainly by promoting rapid ER degradation and elimination. However, recent studies show that FULV-bound ER can still translocate to the nucleus and bind DNA, although it appears transcriptionally inert.

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 confirmed that both E2 and FULV promote ER recruitment to DNA, with E2 increasing chromatin accessibility, transcriptional activation, and 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 increased H3K27ac at a subset of ER binding sites. These observations indicate a decoupling between histone acetylation and transcriptional output under FULV treatment.

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 further suggest that FULV's therapeutic effects may extend beyond simple antagonism of ER activity.