Estrogen receptor alpha (ESR1) (ESR1)

Estrogen receptor alpha (ESR1) is a ligand-activated transcription factor that regulates gene expression in response to estrogen, serving as a primary driver in the majority of breast cancers (Robinson et al., 2013). In metastatic settings, the emergence of ESR1 mutations, particularly in the ligand-binding domain (e.g., Y537S, D538G), leads to constitutive receptor activation and resistance to aromatase inhibitors (Bidard et al., 2022). These mutations function as "hotspot" neoantigens because they are tumor-specific and can be recognized by the immune system when presented as peptides on HLA molecules (Wang et al., 2019). Therapeutic strategies focusing on the ESR1 mutant-specific T-cell response aim to utilize adoptive cell transfer or vaccines to direct the patient's immune system against these resistant clones (NCT04102436). While small-molecule inhibitors like elacestrant target the protein's biochemical activity, neoantigen-based approaches offer a highly specific method to eliminate cells that have evolved to bypass traditional endocrine blockade (Lowery et al., 2022). This dual relevance as both a signaling hub and an immunological target makes ESR1 a focal point for overcoming endocrine resistance in oncology.

Other names

ER-alphaNR3A1Estrogen receptor 1ESRER

Selective estrogen receptor degradation (SERD), selective estrogen receptor modulation (SERM), and T-cell mediated cytotoxicity via MHC-restricted recognition of mutant ESR1 epitopes (Wang et al., 2019; Bidard et al., 2022).