Dataset Information

Targeting the ERα DBD-LBD interface with mitoxantrone disrupts receptor function through proteasomal degradation

ABSTRACT: The estrogen receptor (ER or ERα) remains the primary therapeutic target for luminal breast cancer, with current treatments centered on competitive antagonists, receptor down-regulators, and aromatase inhibitors. This therapeutic landscape frames our discovery of an alternative mechanism of ER inhibition that targets the critical interface between the DNA-binding domain (DBD) and ligand-binding domain (LBD) of the receptor. We identified mitoxantrone (MTO), an FDA-approved topoisomerase II inhibitor, as a specific ligand for this previously unexplored DBD-LBD interface. Through integration of computational, biophysical, biochemical, and cellular analyses, we demonstrate that independent of its DNA damage response activity, MTO binding induces ER conformational changes, leading to cytoplasmic redistribution and proteasomal degradation. Notably, MTO also effectively inhibits constitutively active ER mutants (Y537S and D538G) commonly associated with endocrine therapy resistance, suppressing ER/ER-mutant-dependent gene expression and tumor growth more potently than fulvestrant. These findings establish the DBD-LBD interface as a crucial regulatory point for ER function, suggesting a new paradigm for targeting domain interfaces across the nuclear receptor family.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303561 | GEO | 2025/07/24

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of AR signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splicing variants (AR-Vs) lack the AR ligand-binding domain (AR-LBD), the intended target of androgen deprivation therapies (ADT) including new CRPC therapies such as abiraterone and MDV3100. While the canonical full-length AR (AR-FL) and AR-Vs are both increased in CRPC, their expression regulation, associated transcriptional programs, functional relationships, and respective roles in mediating responses to endocrine therapies have not been dissected. In this study, we show that suppression of canonical AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPC. Importantly, treatment-induced AR-Vs activate a distinct expression signature enriched for cell cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppresses the AR-V signature but activates expression programs mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 and abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, parallels increased expression of the AR-driven cell cycle gene UBE2C. In addition, protein expression of AR-V7, but not AR-FL, is positively correlated with UBE2C in clinical CRPC specimens. The cumulative in vitro and in vivo evidence support an adaptive shift toward AR-V-mediated signaling in at least a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting an important mechanism contributing to drug resistance to CRPC therapies. LNCaP cells lacking AR-V were transfected with AR-V7 with or without androgen stimulation of AR-FL (4 conditions); LNCaP95 cells expressing AR-Vs were treated with control siRNA or siRNA trageting AR-LBD or AR-DBD, with or without androgen stimulation of AR-FL (6 conditions); VCaP cells expressing AR-Vs in the presence of androgen were treated with control siRNA, siRNA trageting AR-LBD, DMSO or MDV3100 to inhibit AR-FL (4 conditions). Total 14 arrays with no replicates.

Dataset Information

Targeting the ERα DBD-LBD interface with mitoxantrone disrupts receptor function through proteasomal degradation

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets