MCF7-ESR1-G521S-Y537S-KI Cell Line

ESR1-G521S-Y537S is a complex, double mutation in the estrogen receptor alpha (ERα) gene, combining a glycine-to-serine substitution at codon 521 within the ligand-binding domain (LBD) with the well-characterized activating Y537S mutation. This dual alteration represents a rare but clinically significant variant associated with profound endocrine therapy resistance in hormone receptor-positive breast cancer. The G521S mutation, located near the helix 11-12 region, may synergize with Y537S to further stabilize the active conformation of ERα, enhance constitutive transcriptional activity, and alter coregulator recruitment beyond that observed with single mutations. Mechanistically, the double mutation confers resistance to a broader spectrum of endocrine agents, including selective estrogen receptor degraders (SERDs) like fulvestrant and next-generation oral SERDs, while potentially retaining sensitivity to selective estrogen receptor covalent antagonists (SERCAs) and proteolysis-targeting chimeras (PROTACs). Detection of complex ESR1 mutations, including G521S-Y537S, in circulating tumor DNA (ctDNA) is associated with poor prognosis, rapid disease progression, and limited response to conventional endocrine therapies. These compound mutations often arise under sequential endocrine treatment pressure through clonal evolution and represent a formidable challenge in precision oncology. Understanding the structural and functional consequences of such double mutations is critical for developing effective therapeutic strategies for heavily pretreated, endocrine-resistant breast cancer.