Progesterone Receptor (PR)

Characteristics

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 (Fig. 1a, uterus and ovary but is also found in other tissues such as endocrine cells of the Langerhans' islets (Fig. 1b)

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.

Neoplasms

PR is predominantly expressed in tumours of female sex steroid responsive tissues such as the mammary gland (Fig. 2a), 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 (Fig. 2b), 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.

Application

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).

Visualization

Several monoclonal antibodies raised against native or recombinant PR protein are available for immunohistochemical demonstration, identifying both isoforms. For best results in paraffin sections, this is performed using HIER. PR is seen in nuclei of target cells mentioned above. Heterogeneity of the staining, both in terms of location and intensity, is common in tumours.

In breast carcinoma, epithelial cells of both ductal and lobular origin display nuclear staining.

Although some studies favour the use of simple negative to three plus scoring, it is advisable to use a histoscore with more systematic semiquantitative evaluation or automated image analysis.

Control: uterine cervix: the stromal cells and basal squamous epithelial cells should show a distinct nuclear reaction with minimal cytoplasmic staining. Normal breast epithelial cell nuclei may also serve as internal or external control but is possibly less reliable than cervix.

Assessments

Run 10 2004

Run B2 2006

Run B4 2007

Run B6 2008

Run B9 2010

Run B12 2011

Selected references

ASCO Expert Panel. Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. J Clin Oncol 1996; 14:2843-2877.

Bardou V-J, Arpino G, Elledge RM, et al. Progesterone  receptor status significantly improves outcome prediction over estrogen receptors status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol 2003;21:1973-1979.

Early Breast Cancer Trialist’s Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998;351:1451-1467.

Elledge RM, Green S, Pugh R et al. Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: A Southwest Oncology Group Study. Int J Cancer 2000;89:111-117.

Graham JD,  Clarke CL. Expression and transcriptional activity of progesterone receptor A and progesterone receptor B in mammalian cells.  Breast Cancer Res 2002;4:187-190.

Hähnel R. Estrogen and progesterone receptor assay in the management of breast and other cancers. Rev Endocr Rel Cancer 1985;20:5-11.

McCarty KS Jr, et al. Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 1985;109:716-721.

McGuire WL, Clark GM. Role of progesterone receptors in breast cancer. Semin Oncol 1985;12:12-16.

Osborne CK, Yochomowitz MG, Knight WA, McGuire WL. The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer 1980;46:2884-288

Press MF, Greene GL. Localization of progesterone receptor with monoclonal antibodies to the human progestin receptor. Endocrinology 1988;122:1165-1175.