Estrogen receptor alpha (ERα) (ERα)

Estrogen receptor alpha (ERα), encoded by the ESR1 gene, is a ligand-activated transcription factor that plays a central role in the development and maintenance of the female reproductive system, bone density, and cardiovascular health (UniProt P03372). It functions by binding to estrogen response elements (EREs) in the DNA, thereby regulating the expression of genes involved in cell proliferation and survival (PubMed: 29129575). In the context of breast cancer, ERα is expressed in approximately 70% of cases and serves as a primary driver of tumor growth (NIH: Breast Cancer Treatment). While endocrine therapies like tamoxifen and fulvestrant have been the standard of care, the emergence of ESR1 mutations—most notably Y537S and D538G—presents a significant clinical challenge. These mutations occur within the ligand-binding domain, leading to constitutive, ligand-independent transcriptional activity and resistance to conventional aromatase inhibitors and certain SERMs (PubMed: 33168636). Consequently, the development of oral selective estrogen receptor degraders (SERDs) like elacestrant has become a priority to target both wild-type and mutant forms of the receptor in advanced or metastatic disease (FDA: Elacestrant Approval).

Other names

ESR1Estrogen receptor 1NR3A1Nuclear receptor subfamily 3 group A member 1ER-alpha

Selective Estrogen Receptor Modulators (SERMs) act as competitive antagonists or agonists in a tissue-specific manner; Selective Estrogen Receptor Degraders (SERDs) bind to the receptor and induce its ubiquitination and subsequent proteasomal degradation, effectively reducing receptor protein levels.