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Estrogen Receptor (ER) alpha

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 (E
2), on growth, differentiation and function in several target tissues, including female and male reproductive tract, mammary gland, and skeletal and cardiovascular systems. Immunohistochemical demonstration of ERα in normal tissues is illustrated in Fig. 1.

Recently, a second estrogen receptor, termed ERβ, was discovered.  Human ERβ shares a high structural homology with the previously known human ER, now termed ERα, 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  ERβ is similar to that of ERα with some differences. In normal and malignant human breast tissue  ERβ is expressed in stromal cells in addition to epithelia. Only limited data are available on the role of ERβ in normal and neoplastic  tissues.

α is mainly expressed in tumours of female sex steroid hormone responsive tissues such as the mammary gland, endometrium, and ovary. Immunohistochemical demonstration of ERα in neoplastic tissues is illustrated in Fig. 2. ERα protein is expressed in 60-70% of female breast cancers (ER+/PR- 19-22%; ER+/PR+ 49-53%). Other tumours expressing ERα are meningiomas, salivary gland tumours, some neuroendocrine tumours, and some colorectal and hepatocellular carcinomas.

The applications of immunohistochemical demonstration of ER
α are two-fold. The main clinical use of ERα immunohistochemistry is prediction of response to therapy in breast carcinoma. Tumours expressing both ERα and PR react positively to antiestrogen therapy in 50-70% of cases as against below 10% of those negative for ERα 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 ERα (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
α 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.

Positive staining reaction is seen in nuclei of the cells of the target tissue. In breast carcinoma, epithelial cells of both ductal and lobular origin display nuclear staining. Efficient HIER is mandatory. The mAbs clone 6F11, SP1 (rabbit mAb) and 1D5 can all be used. However, the latter has less affinity than the others and therefore makes heavier demands on the protocol.

Control tissue: Normal breast epithelial cell nuclei are often used as an internal control. However, uterine cervix is an attractive alternative, as the staining reaction in epithelial and stromal cells is readily assessed. A strong staining of the large majority of columnar and squamous epithelial cells should be seen.

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Last update 14-04-2014