Estrogen-independent molecular actions of mutant estrogen receptor 1 in endometrial cancer

Area of Science:

• Molecular Biology
• Genomics
• Cancer Research

Background:

• Estrogen receptor 1 (ESR1) mutations are linked to hormone therapy resistance in breast cancer and poorer outcomes in endometrial cancer.
• Previous studies suggest mutant ESR1 possesses estrogen-independent activity, but experimental data in endometrial cancer is lacking.
• The D538G mutation in ESR1 is common in endometrial cancer and affects its ligand-binding domain.

Purpose of the Study:

• To experimentally investigate the functional consequences of the D538G ESR1 mutation in endometrial cancer.
• To characterize the genomic binding, gene expression, and chromatin accessibility alterations caused by mutant ESR1.

Main Methods:

• Utilized a CRISPR/Cas9 gene-editing system to introduce the D538G mutation into the endogenous ESR1 locus in endometrial cancer cells.
• Epitope tagging of the endogenous ESR1 locus for precise tracking and analysis.
• Assessed ESR1 genomic binding, gene expression profiles, and chromatin accessibility changes.

Main Results:

• The D538G ESR1 mutation confers estrogen-independent genomic binding, distinct from wild-type ESR1.
• Mutant ESR1 significantly impacts gene expression, including nonestrogen-regulated genes, and alters chromatin accessibility.
• These mutant-specific regulatory changes are not mimicked by prolonged estrogen exposure, differentiating them from constitutive ESR1 activity.

Conclusions:

• The D538G ESR1 mutation promotes estrogen-independent activity in endometrial cancer cells.
• Mutant ESR1 induces unique regulatory alterations in endometrial cancer cells that differ from those observed in breast cancer cells.
• These findings highlight the specific role of ESR1 mutations in endometrial cancer pathogenesis.