Hormonal modulation of ESR1 mutant metastasis.

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Estrogen receptor alpha gene (ESR1) mutations are common in ER-positive metastatic breast cancer.
• These mutations confer resistance to aromatase inhibitors, a standard therapy.

Purpose of the Study:

• To investigate the functional consequences of the ESR1 Y537S mutation.
• To explore the role of androgen receptor (AR) signaling in ESR1-mutant breast cancer metastasis.

Main Methods:

• In vitro cell culture models to assess migration and invasion.
• In vivo xenograft studies in mice to evaluate tumor growth and metastasis.
• Analysis of gene expression signatures and protein levels.

Main Results:

• ESR1 Y537S mutation induced epithelial-mesenchymal transition (EMT), enhancing cell migration and invasion.
• Y537S mutant tumors showed resistance to tamoxifen and estradiol withdrawal.
• A nine-gene signature predicted clinical outcomes and lung metastasis.
• Increased AR levels were observed in mutant models; AR agonist inhibited EMT and metastasis.

Conclusions:

• ESR1 Y537S mutation promotes aggressive tumor behavior and therapeutic resistance.
• AR signaling may represent a therapeutic target to inhibit distant metastasis in ESR1-mutant breast cancer.