Progesterone is one of the central regulators of female reproduction. In breast development, progesterone is involved in the formation of lobular-alveolar structures and also affects differentiation in the breast by modulation of milk protein synthesis. In human endometrium, progesterone directs glandular differentiation and glycogenesis, as well as stromal proliferation and development of predecidual cells. The cellular effects of progesterone are mediated through progesterone receptors (PR).
PR, a protein with 946 amino acids, is a ligand-activated transcription factor member of the steroid receptor super family of nuclear receptors. The functional structure is similar to that of estrogen receptor (ER), with considerable sequence homology in the DNA-binding central domain. The presence of a functional ER is required for PR synthesis in the cell.
PR is predominantly expressed in female sex steroid responsive tissues such as the mammary gland, uterus and ovary but is also found in other tissues such as endocrine cells of the Langerhans' islets.
PR exists in two isoforms, PR-A and PR-B, transcribed from two promoters by a single gene. The two PR isoforms are identical except that PR-A lacks 164 amino acids contained at the N-terminal end of PR-B.
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.
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 mnon-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.
The applications of antibodies to PR are similar to those against ER, i.e. diagnosis of PR-positive tumours (often metastasis) and prediction of therapeutic response of breast carcinoma (see description of ER).
As observed in the previous NordiQC assessments of PR, uterine cervix is an appropriate positive control
for evaluation of the sensitivity of PR staining: With an optimal protocol almost all columnar epithelial cells,
the majority of basal squamous epithelial cells and most of the stromal cells must show a strong and
distinct nuclear staining with only a minimal cytoplasmic reaction. No staining must be seen in endothelial
cells and lymphocytes. However, it must be taken into consideration that the PR expression level is
reduced in the uterine cervix of post-menopausal women and especially demonstration of PR in squamous
epithelial cells can be compromised.Tonsillar tissue is recommendable as negative control, in which no
nuclear staining should be seen.
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