Estrogen receptors are intracellular proteins belonging to nuclear hormone family of intracellular receptors. In molecular biology nuclear hormone family of receptors are the ones who could sense steroid and thyroid hormones. In response, these receptors work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism. Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes, hence these receptors are classified as transcription factors. All transcription factors, therefore, have nuclear expression (e.g. TTF1).
ER binds with estrogen (17β-estradiol) to effect further on the DNA. This event functions in several target tissues, including female and male reproductive tract, mammary gland, and skeletal and cardiovascular systems.
There are two different forms of the estrogen receptor, usually referred to as α and β, each encoded by a separate gene (ESR1 and ESR2, respectively). ERα is a much studied receptor and all the work related to ER pertains to this particular form. Therefore, unless specified otherwise ER should be considered as ERα for all practical purposes.
Human ERβ shares a high structural homology with 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.
Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns:
- The ERα is found in endometrium, breast cancer cells, ovarian stromal cells, and the hypothalamus. In males, ERα protein is found in the epithelium of the efferent ducts.
- The expression of the ERβ protein has been documented in ovarian granulosa cells, kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, and endothelial cells.
ERα is mainly expressed in tumours of female sex steroid hormone responsive tissues such as the mammary gland, endometrium, and ovary. Percentage of breast carcinoma cases with expression of ERα shows large range in literature (cite reference). Our own unpublished database shows expression of ERα in 55% of breast carcinoma cases. Other tumours expressing ERα are meningiomas, salivary gland tumours, some neuroendocrine tumours, and some colorectal and hepatocellular carcinomas.
The applications of immunohistochemical demonstration of ERα 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, ERα 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
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.
Nuclear immunostaining for both receptor proteins can be demonstrated in normal breast acini, which serve as internal controls for the testing procedure. In general, approximately 15% to 20% of the luminal epithelial cells in a duct or lobule stain with ER and PR. However, nuclear staining in normal breast tissue is heterogeneous and may vary with the menstrual cycle.