Estrogen receptor alpha (Y537S mutant) (ERα (Y537S))

Estrogen receptor alpha (ERα), encoded by the ESR1 gene, is a ligand-activated nuclear hormone receptor and transcription factor central to the regulation of gene expression by estrogens in many tissues, including breast epithelium. **The Y537S mutation is a missense somatic mutation within the ligand-binding domain (LBD) of ERα that replaces tyrosine at position 537 with serine.** This mutation is predominantly found in hormone receptor-positive metastatic breast cancer and is linked to acquired resistance to endocrine therapies. Y537S ERα stabilizes the receptor in an agonist (active) conformation even in the absence of hormone, promoting constitutive recruitment of coactivators and continuous expression of estrogen-responsive genes. This results in **estrogen-independent tumor growth and significant resistance to antiestrogen treatments** such as tamoxifen and fulvestrant. Tumors harboring this mutation are typically more aggressive, have altered metabolic programming, and are associated with poor clinical outcome. The mutation poses a substantial therapeutic challenge and is a recognized biomarker of resistance in breast cancer treatment.

Other names

ERα Y537SESR1 Y537SEstrogen receptor 1 (Y537S mutant)Mutant ESR1 Y537S

Antagonism of estrogen binding (reduced efficacy in mutant) Induction of receptor degradation (partially resistant to SERDs) Inhibition of transcriptional coactivator recruitment (reduced by mutation) Antiestrogens block ER-mediated gene expression (reduced efficacy in mutant)