Targeting unique ligand binding domain structural features downregulates DKK1 in Y537S ESR1 mutant breast cancer cells.

ABSTRACT: Resistance to endocrine therapies remains a major clinical hurdle in breast cancer. Mutations to estrogen receptor alpha (ERα) arise after continued therapeutic pressure. Next generation selective estrogen receptor modulators and degraders/downregulators (SERMs and SERDs) show clinical efficacy, but responses are often non-durable. A tyrosine to serine point mutation at position 537 in the ERα ligand binding domain (LBD) is among the most common and most pathogenic alteration in this setting. It enables endocrine therapy resistance by superceding intrinsic structural-energetic gatekeepers of ER hormone-dependence, it enhances metastatic burden by enabling neomorphic ER-dependent transcriptional programs, and it resists SERM and SERD inhibiton by reducing their binding affinities and abilit

SUBMITTER: Young KS 

PROVIDER: S-EPMC11742495 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature