Progesterone receptor
(PgR, PR)

Progesterone resistance

Gene: maps to 11q22-23 (Rousseau-Merck M.F. et al., 1987).
mRNA: sizes: in a series of breast tumours, 4 PgR mRNA species with estimated sizes of 11.4, 4.5, 3.7 and 2.5 kb were detected were detected in 14% of the PgR mRNA-positive tumors. The 3.7-kb transcript was detected to varying degrees in all PgR mRNA-positive biopsies, accompanied in some tumors by the 2.5-kb species. (Nagai M.A. et al., 1994).
Protein: three isoforms (PgR-A, PgR-B, PgR-C) have been identified (Wei L.L. and Miner R., 1994).

Cell lines:
- PgR expression vectors were transfected into estrogen receptor (ER)-alpha and PgR-negative breast cancer cells MDA-MB-231; thus the functions of progesterone could be studied independent of estrogens and ERs. Eight stable transfectant clones expressing both PgR isoform A and B were studied for their growth response to progesterone and its analogues. Although progesterone had no effect on growth in the control transfectant, the hormone markedly inhibited DNA synthesis and cell growth in all of the PgR-transfectants dose-dependently from 10^-12-10^-6 M. This growth inhibition was associated with an arrest of cells in the G₀/G₁ phase of the cell cycle. Progestins medroxyprogesterone acetate, Org2058, and R5020 also strongly inhibited DNA synthesis, and their doses required for maximal inhibition of 60-70% were 10^-17 M, 10^-13 M, and 10^-7 M, respectively. Antiprogestin ZK98299 alone had no effect, but the compound was capable of counteracting the inhibitory effect of progesterone. In contrast, RU486 inhibited DNA synthesis, and it showed no further effects when it was used concurrently with progesterone (Lin V.C. et al., 1999).

- In MDA-MB-231 BCC transfected with PgR, progesterone markedly inhibited cell growth and induced changes in cell morphology and specific adhesion structures. Progesterone-treated cells became considerably more flattened and well spread than vehicle-treated control cells. This was associated with a striking increase of stress fibers, both in number and diameter, and increased focal contacts as shown by the staining of focal adhesion proteins paxillin and talin. There were also distinct increases in tyrosine phosphorylation of focal adhesion protein paxillin and focal adhesion kinase in association with increased focal adhesion. The staining of tyrosine-phosphorylated proteins was concentrated at focal adhesions in progesterone-treated cells. More interestingly, monoclonal antibody (Ab) to beta1 integrin was able to inhibit progesterone-induced cell spreading and formation of actin cytoskeleton (Lin V.C. et al., 2000).

Tumors:
- The expression of estrogen (ER) and progesterone (PgR) receptors was analyzed in a retrospective series of 3000 patients who had operable primary breast cancer. Patients were stratified according to ER and PgR status and the study was focused on the two groups (ER-PgR+ and ER-PgR-) of patients whose tumors contained low levels of ER (< 15 fmol/mg protein), regarding potential response to endocrine therapy. The comparison of clinical or histological characteristics between ER-PgR+ and ER-PgR- patients was analyzed as well as the disease-related death and survival. The mean follow-up was 86.3 months. Among the 529 ER-patients, 62 were PgR+ (12%), whereas 467 were PgR- (88%). The ER-PgR+ and ER-PgR- populations represented 2% and 15.6% of the overall population, respectively. In ER- tumors, the PgR status was significantly related to: age, menopausal status, tumor size, SBR grade, and histological type, but not to the type of surgical treatment or to lymph node involvement. ER-PgR+ tumors had smaller size (64% T1 vs 43%) (p=0.004) and were more frequently grade I (28% vs 12%) than ER-PgR- tumors (p < 0.001). In addition, the patients with ER-PgR+ tumors were significantly younger (49.4 years vs 58.4 years; p < 0.0001), and were more frequently premenopausal (76% vs 36%, p < 0.001). The disease-free interval and the metastasis-free survival tended to be worse for ER-PgR- than for ER-PgR+ patients, but the difference was not statistically significant at 10 years. However, a small but significant difference in overall survival, in favor of the PgR+ group, was observed between the two groups during the first 5 years (p=0.03) (Bernoux A. et al., 1998).

- Tumor samples of 240 patients with primary breast cancer were biochemically and immunohistochemically investigated for estrogen receptors (ER) and, in 130 of the samples, for progesterone-receptors (PgR). The biochemical (DCCA) and immunohistochemical assays (ICA) yielded positivity in 71% for ER, and in 44% for PgR. Concordant ER-DCCA and ER-ICA results were obtained in 84%; two thirds of the discordant ER-findings manifested as DCCA-neg/ICA-pos. Concordance in the case of PgR amounted to 72%, and of the discordances 60% were DCCA-neg/ICA-pos. Significant association with postmenopausal status existed only for ER positivity in ICA, whereas ER-DCCA, PgR-DCCA and PgR-ICA were all more or less independent of the menopausal status. The frequency of discordances was independent of menopausal status. Discordance for ER-assays increased significantly near the respective cut-off point; this was not unequivocally true for PgR-assays (Stierer M. et al., 1998).

- The relationship between expression of receptors for oestrogen and progesterone (ER and PR) and disease progression in breast cancer was investigated by comparing immunocytochemical determinations of ER and PR in fine needle aspirates from primary and secondary breast tumours. Rates of receptor expression were significantly higher in primary than in secondary lesions: for ER 63.3% (n = 689) compared with 45.3% (n = 223), and for PR 53.7% (n = 443) compared with 33.1% (n = 121). The effect of menopausal status was examined by subdividing the patient cohort into those over or under the age of 50 years. In both instances, ER expression in secondary tumours was relatively low; however, only postmenopausal patients had significantly lower rates of PR expression in secondary tumours. Consistent with this, an increase in the ER+PR- profile in secondary tumours compared with primary cases from postmenopausal patients was seen, and in a multivariate analysis, a specific absence of PR expression in secondary tumours was revealed. Comparison of ER and PR expression in simultaneously sampled primary tumours and lymph node metastases from the same patient showed that receptor expression was stable with progression to a metastatic site as results were concordant for ER in 92% (n = 88) and PR in 93.8% of cases (n = 65). These results suggest that absence of PR expression in primary breast cancer is associated with disease progression and may be a marker of an aggressive tumour phenotype (Balleine R.L. et al., 1999).

- PgR protein and mRNA (determined by RT-PCR) levels were found to be significantly correlated in a series of 51 breast tumors. The mRNA levels for ER, PgR, and pS2 in breast tumors (n=100) were significantly correlated to each other, but none of them was associated with the mRNA expression of PAI-1. With respect to clinical data, ER and PgR mRNA were found to be inversely correlated to tumor size and histological grade, but not to the lymph node status (Tong D. et al., 1999).

- A significant inverse correlation between PgR and MMP1 expression in breast tumors has been described (Nakopoulou L. et al., 1999).

Balleine R.L. et al. (1999) Absence of progesterone receptor associated with secondary breast cancer in postmenopausal women. Br. J. Cancer 79, 1564-1571.
Bernoux A. et al. (1998) Estrogen receptor negative and progesterone receptor positive primary breast cancer: pathological characteristics and clinical outcome. Institut Curie Breast Cancer Study Group. Breast Cancer Res. Treat. 49, 219-225.
Lin V.C. et al. (1999) Progestins inhibit the growth of MDA-MB-231 cells transfected with progesterone receptor complementary DNA. Clin. Cancer Res. 5, 395-403.
Lin V.C. et al. (2000) Progesterone induces focal adhesion in breast cancer cells MDA-MB-231 transfected with progesterone receptor complementary DNA. Mol. Endocrinol. 14, 348-358.
Misrahi M. et al. (1987) Complete amino acid sequence of the human progesterone receptor deduced from cloned cDNA. Biochem. Biophys. Res. Commun. 143, 740-748.
Nagai M.A. et al. (1994) Estrogen and progesterone receptor mRNA levels in primary breast cancer: association with patient survival and other clinical and tumor features. Int. J. Cancer 59, 351-356.
Nakopoulou L. et al. (1999) Matrix metalloproteinase-1 and -3 in breast cancer: correlation with progesterone receptors and other clinicopathologic features. Hum. Pathol. 30, 436-442.
Rousseau-Merck M.F. et al. (1987) Localization of the human progesterone receptor gene to chromosome 11q22-q23. Hum. Genet. 77, 280-282.
Stierer M. et al. (1998) Comparison of immunohistochemical and biochemical measurement of steroid receptors in primary breast cancer: evaluation of discordant findings. Breast Cancer Res. Treat. 50, 125-134.
Tong D. et al. (1999) Messenger RNA determination of estrogen receptor, progesterone receptor, pS2, and plasminogen activator inhibitor-1 by competitive reverse transcription-polymerase chain reaction in human breast cancer. Clin. Cancer Res. 5, 1497-1502.
Wei L.L. and Miner R. (1994) Evidence for the existence of a third progesterone receptor protein in human breast cancer cell line T47D. Cancer Res. 54, 340-343.