Estrogen receptor (ER) belongs to the steroid receptor superfamily of nuclear receptors. It is a protein with 553 amino acids. The receptor molecule has three domains, i.e. the central DNA-binding domain, the hormone-binding domain at the C-terminal, and the transcription-activating domain at the N-terminal. ER mediates regulatory functions of female sex steroids, mainly 17 (E2), on growth, differentiation and function in several target tissues, including female and male reproductive tract, mammary gland, and skeletal and cardiovascular systems. Recently, a second estrogen receptor, termed ER?, was discovered. Human ER? shares a high structural homology with the previously known human ER, now termed ER?, especially in the DNA- and hormone binding domains. Both receptors bind hormones with similar affinity and their transcriptional activation is identical. The tissue distribution of ER? is similar to that of ER? with some differences. In normal and malignant human breast tissue ER? is expressed in stromal cells in addition to epithelia. Only limited data are available on the role of ER? in normal and neoplastic tissues.
ER? is mainly expressed in tumours of female sex steroid hormone responsive tissues such as the mammary gland, endometrium, and ovary. ER? protein is expressed in 60-70% of female breast cancers (ER+/PR- 19-22%; ER+/PR+ 49-53%). Other tumours expressing ER? are meningiomas, salivary gland tumours, some neuroendocrine tumours, and some colorectal and hepatocellular carcinomas.
The applications of immunohistochemical demonstration of ER? are two-fold. The main clinical use of ER? immunohistochemistry is prediction of response to therapy in breast carcinoma. Tumours expressing both ER? and PR react positively to antiestrogen therapy in 50-70% of cases as against below 10% of those negative for ER? and PR. Based on these facts and a number of meta-analyses, adjuvant antiestrogen treatment is administered in most countries to postmenopausal women with ER+ breast cancer. In addition to predicting treatment response, the ER? (and PR) status can be used to estimate disease-free and overall survivals of breast carcinoma patients. In newer studies with immunohistochemical assay, positive steroid hormone status has predicted favourable overall, survival, independently of hormonal treatment. Secondly, ER? can be used as a tumour marker (see Neoplasms above), preferentially in combination with an antibody to Progesterone receptor, e.g., in the classification of adenocarcinomas.
Uterine cervix and tonsil can be recommended as positive tissue controls for ER. In uterine cervix, virtually all squamous and columnar epithelial cells must show a moderate to strong and distinct nuclear staining reaction. Lymphocytes and endothelial cells must be negative.
Tonsil is especially found recommendable as a tool to monitor the level of analytical sensitivity for the demonstration of ER. Dispersed follicular dendritic cells in germinal centers and squamous epithelial cells must show an at least weak but distinct nuclear staining reaction. In addition, tonsil can be used as negative tissue control, as B-cells in mantle zones and within germinal centers must be negative.
To validate the specificity of the IHC protocol further, an ER negative breast carcinoma must be included as primary negative tissue control, in which only remnants of normal epithelial and stromal cells should be ER positive, serving as internal positive tissue control. Positive staining reaction of the stromal cells in breast tissue indicates that the IHC protocol provides a high analytical sensitivity for ER, whereas the analytical sensitivity cannot reliably be evaluated in normal epithelial cells in breast as they typically express moderate to high levels of ER.