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

Multiple next-generation molecules targeting estrogen receptor α (ERα) are being investigated in breast cancer clinical trials, encompassing thousands of women globally. Development of these molecules was partly motivated by the discovery of resistance-associated mutations in ESR1 (encodes ERα). Here, we studied the impact of ERα antagonist/degraders against Esr1 mutations expressed in mouse mammary glands. Inhibition of mutant ERα induced mixed-lineage cells, characterized by aberrant co-engagement of normally disparate master transcription factors. Lineage infidelity was also observed in Esr1-wild-type mice upon long-term estrogen deprivation. In ER⁺ breast cancer biopsy specimens, heavily pretreated tumors with no ESR1 mutation detected (NMD) frequently exhibited mixed-lineage features. ESR1-mutant tumors generally retained luminal features and higher ERα activity and exhibited an anti-proliferative response to the ERα antagonist giredestrant. ESR1-mutant tumors acquired mixed-lineage features following treatment. Lineage heterogeneity in advanced ER⁺ breast cancer may underpin the differential benefit of investigational ERα therapeutics observed in ESR1-mutant versus NMD contexts.