ESR1, the gene encoding estrogen receptor (ER) α, is mutated in hormone-resistant breast cancer.
Major finding: ESR1, the gene encoding estrogen receptor (ER) α, is mutated in hormone-resistant breast cancer.
Concept: Ligand-binding domain mutations lead to constitutive ERα activity and reduce hormonal therapy efficacy.
Impact: Patients with ESR1 mutations may respond to alternate therapies that target ER signaling.
Hormone therapy, an inclusive term for drugs that inhibit estrogen receptor (ER) signaling or block estrogen production, is initially effective in the approximately 70% of patients with breast cancer who have ER-positive tumors, but many patients develop resistance after long-term drug exposure. Toy and colleagues performed sequencing and copy number analysis of commonly mutated genes in tumors from patients with metastatic ER-positive breast cancer who progressed while on hormone therapy to identify potential resistance mechanisms, and Robinson and colleagues performed whole-exome sequencing of patients with hormone-resistant metastatic ER-positive breast cancer enrolled in a clinical sequencing program to identify actionable mutations for personalized therapy. Remarkably, both groups identified recurrent mutations affecting the ligand-binding domain of estrogen receptor 1 (ESR1), the gene encoding ERα, that were not observed in unselected or untreated populations. These ERα mutants had markedly increased transcriptional activity in the absence of ligand and promoted hormone-independent tumor growth after estrogen deprivation in vivo. Consistent with these findings, structural analyses indicated that the mutant proteins adopted a conformation similar to agonist-bound wild-type ERα regardless of the presence of ligand. ER antagonists such as tamoxifen or fulvestrant were still effective against the ligand-binding domain ERα mutants, but Toy and colleagues noted that the mutant proteins retained a significant amount of residual activity and required higher drug doses than wild-type ERα for full inhibition. Although studies of larger cohorts of patients with ER-positive breast cancer before and after hormone therapy will be needed to determine the frequency of acquired ESR1 mutations, these studies implicate mutations in the ligand-binding domain of ERα as a potential hormone therapy resistance mechanism and suggest that patients with activating ESR1 mutations may benefit from more potent or selective ER antagonists or alternate therapies that target ER signaling.
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