Estrogen receptor alpha Y537S mutant (ERα-Y537S)

The Estrogen receptor alpha (ERα) Y537S mutant is a constitutively active variant of the ERα protein, encoded by the ESR1 gene, which plays a critical role in the progression of endocrine-resistant breast cancer [1, 5]. This specific somatic mutation involves a tyrosine-to-serine substitution at position 537 within the ligand-binding domain, which stabilizes the receptor in an agonist-like conformation [1, 12]. Consequently, the mutant receptor recruits coactivators and initiates gene transcription independently of estrogen, driving uncontrolled cell proliferation even under conditions of estrogen deprivation [2, 10]. Clinically, the Y537S mutation is frequently detected in metastatic, ER-positive breast cancers that have progressed on aromatase inhibitors or tamoxifen, serving as a primary mechanism of acquired resistance [6, 15]. While traditional therapies like fulvestrant show reduced efficacy against this mutant, newer oral selective estrogen receptor degraders (SERDs) such as elacestrant have been specifically approved to target ESR1-mutated tumors [5, 14]. Ongoing research also explores combining these agents with CDK4/6 or BET inhibitors to overcome the aggressive growth and therapeutic evasion associated with this mutation [2, 9].

Other names

ESR1 Y537SEstrogen receptor 1 Y537SER-alpha Y537Sp.Tyr537Ser

Selective estrogen receptor degradation, selective estrogen receptor modulation, complete estrogen receptor antagonism, and inhibition of transcriptional coactivator recruitment.