- Gene: ESR1 encodes the estrogen receptor alpha (ERα) protein.
- Location: Chromosome 6q25.1
- Function:
The estrogen receptor is a nuclear hormone receptor that binds estrogen, then regulates gene transcription to promote cell proliferation and survival, especially in breast tissue.
Clinical Significance in Breast Cancer
- Role:
ESR1 expression defines ER-positive breast cancer, making tumors responsive to endocrine therapy. - ESR1 Mutations:
- Acquired mutations (often in the ligand-binding domain) can develop during or after endocrine therapy.
- These mutations cause constitutive activation of the estrogen receptor, leading to endocrine therapy resistance (tumor grows despite low estrogen levels or anti-estrogen drugs).
- Common ESR1 mutations: Y537S, D538G.
- Testing:
Detection of ESR1 mutations (via tissue biopsy or circulating tumor DNA) can guide treatment decisions, such as use of next-generation SERDs (e.g., elacestrant) or other agents effective against resistant disease.
Therapeutic Implications
- Presence of ESR1 mutations often indicates resistance to aromatase inhibitors.
- SERDs like fulvestrant and elacestrant can degrade mutant ER and retain efficacy.
- Emerging targeted therapies aim to overcome ESR1 mutation-driven resistance.