The ESR1 gene at 6q25.1-q25.2 codes for the 595 amino acid oestrogen receptor (ER) whose ligand is oestrogen. This is a nuclear hormone receptor with a DNA binding site that is very similar to oestrogen receptor beta coded by the ESR2 gene with which it can form heterodimers. There are several isoforms and these various and complex interactions are well characterised. Like other steroid receptors it is involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues.
The ER has three domains:
- a modulating N-terminal domain
- called the A/B or AF-1 domain
- ligand-independent transactivation function
- provides the major transactivation function in differentiated cells
- a DNA-binding domain
- a C-terminal ligand-binding domain.
- called the E/F or AF-2 domain
- ligand-dependent transactivation domain
Mutations in the gene cause oestrogen resistance (estrogen resistance , ESTRR, OMIM:615363) with absence of the pubertal growth spurt but continued growth into adulthood and very tall adult stature. There is delayed bone maturation and unfused epiphyses, with osteoporosis. Glucose intolerance, hyperinsulinaemia and lipid abnormalities can also occur.
Significance in breast cancer
The protein expression of ER-α can be assessed using immunohistochemistry. The intensity of staining and the proportion of tumour cells staining positive is typically assessed using the Allred score (also known a the quick/Quick score). For more nuanced measurements, the more time-consuming H-score is used. About 75% of breast cancers are ER+, which respond to hormonal blockade either with oestrogen antagonists (e.g. tamoxifen), but also with aromatase inhibitors (e.g. anastrazole or letrozole)), the latter more important in post-menopausal women where a significant about of oestrogen is produced by adipose tissue.
Significance in pharmacology
The selective estrogen receptor modulators (SERMs) have tissue selective agonistic and antagonistic effects on the oestrogen receptor (ER), interfering with its association with coactivators or corepressors, mainly involving the AF-2 domain.