Targeting the ERα DBD-LBD Interface with Mitoxantrone Disrupts Receptor Function through Proteasomal Degradation

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Estrogen receptor (ERα) is a key target in luminal breast cancer.
• Current ER therapies face resistance, necessitating novel strategies.
• The interface between ER's DNA-binding domain (DBD) and ligand-binding domain (LBD) is unexplored.

Purpose of the Study:

• To identify novel ER inhibition mechanisms.
• To find ligands targeting the ER DBD-LBD interface.
• To develop strategies overcoming endocrine therapy resistance.

Main Methods:

• Computational screening and functional assays.
• Biophysical, biochemical, and cellular analyses.
• In vitro and in vivo xenograft models.

Main Results:

• Mitoxantrone (MTO) identified as a specific ligand for the ER DBD-LBD interface.
• MTO induces ER conformational changes, cytoplasmic redistribution, and proteasomal degradation.
• MTO potently inhibits wild-type and resistant ER mutants, suppressing tumor growth.

Conclusions:

• The ER DBD-LBD interface is a druggable allosteric site.
• MTO offers a new therapeutic paradigm by disrupting interdomain communication.
• This approach overcomes conventional ER resistance mechanisms.