Estrogen receptors (ERs) are a group of receptors that are activated by the estrogen (17 beta estradiol) hormone. There are two major types of estrogen receptors; the prominent one being the ER protein, which belongs to the nuclear hormone receptor superfamily. ER, itself, occurs in two different forms, ER alpha and ER beta, both coded by separate genes. Both these forms show a great amount of homology. The ESR1 gene codes for the ER alpha receptor. The hormone estrogen plays a central role in several cellular processes, including growth, differentiation, and reproductive function. These functions of estrogen are carried out by its binding to the estrogen receptor. Once bound by the ligand, the receptor undergoes a dimerization process, followed by transport to the nucleus. Within the nucleus, the activated ER-dimer binds to specific sites in the DNA, known as the estrogen response elements (ERE). The EREs are located in the promoter region of target genes and transactivates these genes.
Apart from their role in normal cellular functioning, estrogen receptors are also involved in certain pathological processes, including breast and endometrial cancer, and osteoporosis. In fact, around 70% of breast cancers are ER-positive, i.e., have an over-expression of ER. In such cases, the tumors tend to respond very well to treatment with selective estrogen receptor modulators, such as tamoxifen.
The ESR1 gene, located on chromosome 6q codes for the ER alpha. The gene is made up of eight exons and spans a length of 473 Kb. The 66 kDa ER alpha protein consists of five domains. The C domain binds to the DNA, while the E domain contains the hormone binding site and sites for the coactivator and corepressor proteins. The E domain, thus, is the one that carries out the actual activation of gene transcription. The cytoplasmic A/B domain can also carry out transcription in the absence of ligand binding, although this activity is very weak. The unbound receptor is generally localized to the cytoplasm, although it is also available in the nucleus.
Splice variants exist for both alpha and beta ERs. Estrogen function, thus, results from a balance between the wild-type ERs and their variants. ERs are mostly expressed in the endometrium, breast, ovarian stroma, and the hypothalamus.
Nasralla et al. (1992) studied ER levels in 132 primary breast cancer tissue specimens. An inverse significant correlation was observed between ERc and ERn levels vs. epidermal growth factor receptor levels in tumors of post-menopausal women. No such correlation could be seen in pre-menopausal patients. While EGFR positive tumors showed no significant difference in the levels of ER in premenopausal and postmenopausal women, EGFR negative tumors showed a significantly higher value in the postmenopausal women.
Al-Bader et al. (2010) analyzed 40 formalin-fixed paraffin-embedded breast cancer samples to detect wild-type or exon-deleted 3, 5, 6 and 7 variants of alpha estrogen receptor and wild-type ER?1 and ER?2 and ER?5 variants. Many samples expressed both wild-type ER isoforms and their variants.