Estrogen receptor alpha (mutant) (ERα (mutant))

Mutant Estrogen receptor alpha (ERα), encoded by the ESR1 gene, is a major driver of acquired endocrine resistance in metastatic ER-positive breast cancer (Robinson et al., 2013; UniProt: P03372). These mutations, most commonly occurring at residues Y537 and D538 within the ligand-binding domain, result in a constitutively active receptor that functions independently of its natural ligand, estradiol (Toy et al., 2013). This ligand-independent signaling allows tumor cells to continue proliferating despite treatment with aromatase inhibitors, which only target estrogen production. Therapeutic intervention requires specialized agents like elacestrant, a Selective Estrogen Receptor Degrader (SERD) that can effectively bind to and degrade the mutant protein to halt tumor growth (FDA, 2023). Clinical detection of these mutations is increasingly performed using liquid biopsies to analyze circulating tumor DNA (ctDNA), providing a non-invasive method to guide treatment transitions in the metastatic setting (Bidard et al., 2022). Targeting the mutant receptor remains a primary focus of drug development to overcome the limitations of traditional endocrine therapies.

Other names

ESR1 mutantMutant ER-alphaEstrogen receptor 1 (mutant)ER-alpha LBD mutationsConstitutively active Estrogen receptor alpha

Antagonism and proteasomal degradation of the estrogen receptor to inhibit constitutive, ligand-independent transcriptional activity (Jeselsohn et al., 2015; FDA, 2023).