Progesterone 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).
PR binds with progesterone to effect further on the DNA. This event functions in several target tissues, including mammary gland and endometrium.
There are two different forms of the estrogen receptor, usually referred to as α and β, both encoded by a single gene. One of the effects of estrogen is to induce the PR, and thus the coordinate expression of both hormones in the same cell reflects the fidelity of the ER/PR axis in the cell. In carcinomas of the breast, most PR-positive tumors are also ER positive, and ER-negative, PR-positive tumors account for fewer than 1% of all breast cancers.
In human tissues PR-A and PR-B are usually co-expressed equivalently. Predominant expression of one isoform occurs in some tissues and circumstances. PR-A is the major isoform in the uterine stroma, and PR-B is the predominant isoform in the endometrial glands. Normal human breast expresses PR-A and PR-B to equal extent.
ER and PR bind hormones that exert their effects in the nucleus. 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.
PR is predominantly expressed in tumours of female sex steroid responsive tissues such as the mammary gland, endometrium and the ovary. About half of the breast carcinomas are ER+/PR+. A small fraction (<5%) is ER-/PR+. About half of the non-mucinous ovarian carcinomas are also PR+.
From other PR-expressing tumours, meningiomas, various pancreatic neoplasms such as solid-pseudopapillary tumour and endocrine tumours, and salivary gland neoplasms are worth mentioning.
The ER and PR status has been used for over 20 years as a predictor of breast carcinoma responsiveness to endocrine therapy and as a prognostic indicator for early recurrence. Up to 75% of ER+/PR+ breast carcinomas respond positively to endocrine treatment. ER+/PR- tumours are less responsive, and thus PR status adds information to ER-status. In combination the two predict benefit from endocrine therapy both in adjuvant setting and in advanced disease.
In breast cancer predominance of one isoform, namely PR-B, is common. The majority of endometrial carcinomas express only one isoform.
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.