ERα dysfunction caused by ESR1 mutations and therapeutic pressure promotes lineage plasticity in ER⁺ breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Next-generation estrogen receptor alpha (ERα) antagonists/degraders are in clinical trials for breast cancer.
• Development is driven by resistance mutations in the ESR1 gene.

Purpose of the Study:

• To investigate the impact of ERα antagonist/degrader therapy on Esr1 mutations in mouse models.
• To analyze lineage plasticity in ER-positive (ER+) breast cancer under different treatment and ESR1 mutation contexts.

Main Methods:

• Studied ERα antagonist/degrader effects on Esr1-mutant and wild-type mouse mammary glands.
• Analyzed ER+ breast cancer biopsy specimens from heavily pretreated patients (ESR1-mutant vs. ESR1-NMD).
• Assessed lineage features, ERα activity, and response to giredestrant.

Main Results:

• Inhibition of mutant ERα induced mixed-lineage cells with aberrant transcription factor co-engagement.
• Lineage infidelity also occurred in Esr1-wild-type mice with long-term estrogen deprivation.
• Heavily pretreated, ESR1-NMD tumors frequently showed mixed-lineage features.
• ESR1-mutant tumors retained luminal features and ERα activity, responding to giredestrant, but acquired mixed-lineage features post-treatment.

Conclusions:

• Lineage heterogeneity is induced by ERα inhibition and estrogen deprivation.
• Mixed-lineage features are common in advanced ER+ breast cancer, particularly in ESR1-NMD tumors.
• Lineage plasticity may explain differential responses to ERα therapeutics in ESR1-mutant versus ESR1-NMD breast cancer.