ESR1

ESR1 is the gene that encodes ERα, a protein belonging to the nuclear receptor superfamily. ESR1 is composed of two activating function domains (AF-1, the N-terminal ligand-independent portion, and AF-2, the C-terminal ligand-dependent portion), which regulate the transcriptional activity of the receptor, a ligand-binding domain (LBD) located in the C-terminal part, a DNA-binding domain, and a hinge domain (PMID: 31795152). The protein localizes to the nucleus where it may form a homodimer or a heterodimer with estrogen receptor 2. Estrogen and its receptors are essential for sexual development and reproductive function, but also play a role in other tissues such as bone. Estrogen receptors are also involved in pathological processes , including breast cancer, endometrial cancer and osteoporosis. ER is expressed in over 60% of breast cancers and consists of two activation function domains, AF1/2, a DNA binding domain and a hinge domain, and a ligand-binding domain (LBD). ER functions as a ligand-dependent transcription factor, and ligand binding to the LBD leads to activation of gene transcription, resulting in breast cancer progression. ESR1 was altered in 8.37% of breast cancer patients. Preclinical and clinical studies have dem- onstrated that ESR1 mutations can preexist in primary tumors and can be enriched during metastasis. Furthermore, ESR1 mutations express a unique transcriptional profile that favors tumor progression, suggesting that selected ESR1 mutations may influence metastasis (PMID: 31318440).

Endocrine therapy is the mainstay of treatment in both local and metastatic HR+ tumors and includes ER inhibition by either ER modulators (i.e., tamoxifen (TAM)), ER degraders (i.e., fulvestrant), or estrogen deprivation by aromatase inhibitors (AI). Thus far, 2 CDK4/6 inhibitors, palbociclib and ribociclib, have been approved to treat metastatic ER+ breast cancer (PMID: 29234250). Clinically, patients with ESR1 mutations derive clinical benefit when treated with fulvestrant and CDK4/6 targeted therapies. However, the development of more potent selective estrogen receptor degraders (SERDs), and, or new targeted biotherapies are needed to overcome the endocrine-resistant phenotype of ESR1 mutant-bearing tumors.