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Query: UNIPROT:P06889 (Mol)
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In order to gain further knowledge on the beta-adrenergic receptor system in DMBA-induced rat mammary tumors, we have studied the correlation between changes in tumoral beta-adrenergic receptor concentration and distribution, progesterone receptor status and tumor growth after ovariectomy and treatment with various ovarian and adrenal steroids, or induction of hyperprolactinemia. Autoradiographic localization of beta-adrenergic receptors in ovariectomized (OVX) animals shows very weak labeling with [125I]cyanopindolol. In these tumors, the connective tissue is predominant, while the epithelial cell content is very low. Similarly, when direct measurements of [125I]cyanopindolol are performed with membrane preparations, beta-adrenergic receptor concentration is sharply reduced 2-3 weeks following ovariectomy or treatment with LHRH against [D-Trp6, des-Gly-NH2(10)]LHRH ethylamide. This effect on the beta-adrenergic receptor population in the tumor is accompanied by the well known effect of castration on tumor growth and progesterone receptor levels, namely a marked regression of tumor growth and a significant decrease in progesterone receptor concentration. Treatment of OVX rats with 17 beta-estradiol (E2) alone or in combination with progesterone (P) caused a highly significant increase in beta-adrenergic and progesterone receptor levels, as well as tumor growth. A similar sharp increase in the value of the three parameters studied was observed following daily treatment of OVX rats with dehydroepiandrosterone (DHEA) or androst-5-ene-3 beta,17 beta-diol (5-ene-diol). The autoradiographic localization of beta-adrenergic receptors in OVX rats treated with 5-ene-diol showed that the epithelial cells were numerous with a high degree of labeling. On the other hand, treatment of OVX animals with the androgen dihydrotestosterone (DHT) did not produce significant changes in beta-adrenergic receptor levels or tumor growth. Finally, endogenously-induced hyperprolactinemia by implanting three anterior pituitary glands under the kidney capsule of OVX animals resulted in a significant increase in beta-adrenergic and progesterone receptor levels as well as tumor growth. The positive correlation observed between changes in beta-adrenergic receptor concentration, progesterone receptor levels and tumor growth indicates a high sensitivity of the beta-adrenergic receptor population of DMBA-induced rat mammary tumors to the hormonal milieu, and suggests that the beta-adrenergic receptor system may represent a valuable parameter of hormone responsiveness.
J Steroid Biochem Mol Biol 1991 Mar
PMID:A potential role for catecholamines in the development and progression of carcinogen-induced mammary tumors: hormonal control of beta-adrenergic receptors and correlation with tumor growth. 184 92

The effect of two anti-oestrogens, 4-OH tamoxifen and ICI 164,384, on growth and progesterone receptor (PR) concentration was investigated in the endometrial carcinoma cell line, Ishikawa. Growth stimulation in response to 4-OH tamoxifen was antagonized by ICI 164,384, the latter having no agonist effect when used as a single agent. Similarly, ICI 164,384 antagonized oestradiol-stimulated cell growth. PR was significantly increased following treatment with 4-OH tamoxifen, this response being antagonized in the presence of ICI 164,384. Oestradiol increased PR, although to a lesser extent than did 4-OH tamoxifen; the effect of oestradiol on PR was also antagonized by ICI 164,384. Used as a single agent, ICI 164,384 induced a moderate but statistically significant increase in PR, thus demonstrating partial agonist activity. This agonist property of ICI 164,384 may provide a mechanism of maintaining PR, which is down-regulated during conventional progestin therapy, without undesirable mitogenic activity.
J Mol Endocrinol 1991 Jun
PMID:The effect of anti-oestrogens on cell growth and progesterone receptor concentration in human endometrial cancer cells (Ishikawa). 188 84

The binding affinity and relative estrogenic potency of 2-bromo-, 4-bromo-, 2-methyl- and 4-methylestradiol was evaluated in MCF-7 breast cancer cells. The relative binding affinities compared to estradiol were 47% for 2-methyl-, 25% for 4-methyl-, 37% for 4-bromo- and 17% for 2-bromoestradiol. However, both 2- and 4-methyl- as well as 2- and 4-bromoestradiol were able (a) to translocate the cytosolic estrogen receptor into the nucleus and (b) to induce the progesterone receptor in a concentration dependent manner. Finally, all ring-A substituted estrogens used in this study induced the pS2 mRNA as demonstrated by Northern-blotting. From these findings we conclude that 2-bromo-, 4-bromo-, 2-methyl- and 4-methylestradiol are agonistic ligands for the estrogen receptor in MCF-7 breast cancer cells.
J Steroid Biochem Mol Biol 1991 Sep
PMID:Methyl and bromo derivatives of estradiol are agonistic ligands for the estrogen receptor of MCF-7 breast cancer cells. 191 26

The mammalian ribosomal RNA gene promoters exhibit a conserved sequence between positions +1 and +16 that shows a high degree of homology to the response element for glucocorticoids and progestins (GRE/PRE). These sequences bind specifically the glucocorticoid receptor and the progesterone receptor (PR) albeit with lower affinity than a canonical GRE/PRE. Because steroid hormones are known to affect expression of the ribosomal genes, we tested the influence of hormone receptors on the activity of the ribosomal RNA gene promoter in a cell-free transcription assay. Preparations of PR that induce transcription from the mouse mammary tumour virus (MMTV) promoter do not stimulate but slightly inhibit transcription from the ribosomal RNA gene promoter. This weak negative effect is not mediated through binding to the hypothetical GRE/PRE as a mutant promoter that does not bind receptor is equally repressed. Introduction of the functional MMTV GRE/PRE upstream of the basal ribosomal RNA gene promoter does not enhance its transcription in the presence of an active PR. Thus, RNA polymerase I transcription cannot be stimulated in vitro by cis elements and regulatory proteins that are active in RNA polymerase II transcription.
J Steroid Biochem Mol Biol 1991 Oct
PMID:Neither the endogenous nor a functional steroid hormone receptor binding site transactivate the ribosomal RNA gene promoter in vitro. 191 32

We have examined the influence of transforming agents on the in vitro modulation of the 90 kDa heat-shock protein (hsp-90) associated with the calf uterine progesterone receptor (PR). This analysis was facilitated by the use of alpha PR6 (Sullivan et al. 1986) (anti-PR monoclonal antibody that recognizes 110 kDa protein of chicken PR, subunit PR-B), which was seen to shift the rate of sedimentation of the untransformed (8S) and thermally transformed (4S) [3H]R5020-receptor complexes from the calf uterine cytosol toward the bottom of the tube. Silver staining of the alpha PR6-purified calf uterine cytosol revealed the presence of two major proteins with Mr 114 kDa and 90 kDa. Affinity-labeling of uterine cytosol with [3H]R5020, however, yielded only one major protein of 114 kDa. Incubation of uterine cytosol with AC88 (Riehl et al. 1985), a monoclonal antibody that recognizes hsp-90, resulted in a precipitation of a single 90 kDa protein which showed electrophoretic mobility similar to the second protein precipitated with alpha PR6. Western blot analysis confirmed that alpha PR6 interacts only with the 114 kDa cytosol protein representing the calf uterine PR. Incubation of PR complexes at 23 degrees C or at 0 degrees C with 0.3 M KCl or 10 mM ATP also caused the dissociation of hsp-90 from the 114 kDa PR protein, although thermal transformation was less effective in dissociating hsp-90 from PR when the ligand binding site was occupied by the antiprogestin RU486. The presence of iodoacetamide (IA) stabilized the nontransformed RU486-bound PR against thermal transformation while there was dissociation of hsp-90 from the R5020-receptor complexes. Results of our study demonstrate that calf uterine PR is represented by a major steroid binding protein of 114 kDa that exists in association with hsp-90. Exposure to transforming conditions leads to dissociation of receptor-associated hsp-90. Furthermore, the inability of IA-treated RU486-occupied PR to transform suggests that transformation of agonist-bound PR involves SH-groups which must be protected from the inactivating influence of IA.
Mol Cell Biochem 1991 Jun 26
PMID:Immunoanalysis of calf uterine progesterone receptor: modulation of receptor-associated 90 kDa heat-shock protein. f. 192 9

Steroid receptors regulate transcription of target genes in vivo and in vitro in a steroid hormone-dependent manner. Unoccupied progesterone receptor exists in the low-salt homogenates of target cells as a functionally inactive 8 to 10S complex with several nonreceptor components such as two molecules of 90-kDa heat shock protein (hsp90), a 70-kDa heat shock protein (hsp70), and a 56-kDa heat shock protein (hsp56). Ligand-induced dissociation of receptor-associated proteins such as hsp90 has been proposed as the mechanism of receptor activation. Nevertheless, it has not been established whether, beyond release of heat shock proteins, the steroidal ligand plays a role in modulating receptor activity. To examine whether the release of these nonreceptor proteins from receptor complex results in a constitutively active receptor, we isolated an unliganded receptor form essentially free of hsp90, hsp70, and hsp56. Using a recently developed steroid hormone-responsive cell-free transcription system, we demonstrate for the first time that the dissociation of heat shock proteins is not sufficient to generate a functionally active receptor. This purified receptor still requires hormone for high-affinity binding to a progesterone response element and for efficient transcriptional activation of a target gene. When an antiprogestin, Ru486, is bound to the receptor, it fails to promote efficient transcription. We propose that in the cell, in addition to the release of receptor-associated inhibitory proteins, a distinct hormone-mediated activation event must precede efficient gene activation.
Mol Cell Biol 1991 Oct
PMID:Progesterone enhances target gene transcription by receptor free of heat shock proteins hsp90, hsp56, and hsp70. 192 29

This study documents a biphasic change in the rate of cell cycle progression and proliferation of T-47D human breast cancer cells treated with synthetic progestins, consisting of an initial transient acceleration in transit through G1, followed by cell cycle arrest and growth inhibition. Both components of the response were mediated via the progesterone receptor. The data are consistent with a model in which the action of progestins is to accelerate cells already progressing through G1, which are then arrested early in G1 after completing a round of replication, as are cells initially in other phases of the cell cycle. Such acceleration implies that progestins act on genes or gene products which are rate limiting for cell cycle progression. Increased production of epidermal growth factor and transforming growth factor alpha, putative autocrine growth factors in breast cancer cells, does not appear to account for the initial response to progestins, since although the mRNA abundance for these growth factors is rapidly induced by progestins, cells treated with epidermal growth factor or transforming growth factor alpha did not enter S phase until 5 to 6 h later than those stimulated by progestin. The proto-oncogenes c-fos and c-myc were rapidly but transiently induced by progestin treatment, paralleling the well-known response of these genes to mitogenic signals in other cell types. The progestin antagonist RU 486 inhibited progestin regulation of both cell cycle progression and c-myc expression, suggesting that this proto-oncogene may participate in growth modulation by progestins.
Mol Cell Biol 1991 Oct
PMID:Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor alpha, epidermal growth factor receptor, c-fos, and c-myc genes. 192 31

The antirheumatic gold salt aurothiomalate (AuTM) has cellular actions that are consistent with modulation of gene expression. We have tested the hypothesis that an important mode of action of AuTM is inhibition of binding of certain transcription factors to regulatory elements in DNA. The chemistry of transcription factors containing the zinc finger motif makes them candidates for such an interaction with AuTM. In this regard, the interaction of a steroid hormone receptor, the progesterone receptor (PR), with its DNA response element (PRE) was chosen as a suitable model. Nuclear extracts of T-47D human breast cancer cells rich in PR were incubated with radiolabeled PRE, and binding was determined by gel retardation assay. Preincubation of nuclear extract with AuTM caused a concentration-dependent inhibition of binding of PR to PRE (IC50, approximately 3 microM). Other metal ions inhibited binding at higher concentrations, in a rank order correlating with their binding affinity for thiols. Thiomalic acid had no effect in the absence of gold in this system. To test the effect of AuTM on PR-mediated transcription, we transfected the progestin-inducible expression vector pMSG-CAT into T-47D cells. Transfected cells were incubated in the absence or presence of AuTM and treated with the synthetic progestin ORG2058, to induce chloramphenicol acetyl transferase (CAT) activity. With 10 and 100 microM AuTM, there was inhibition to 67 +/- 3% (p = 0.012) and 42 +/- 8% (p = 0.008) of CAT specific activity, respectively, compared with controls. These results demonstrate that AuTM can regulate gene expression and that inhibition of binding of a transcription factor to its response element is a likely mechanism. This provides a molecular model for further study of the antirheumatic action of gold salts.
Mol Pharmacol 1991 Nov
PMID:Inhibition of DNA binding and transcriptional activity of a nuclear receptor transcription factor by aurothiomalate and other metal ions. 194 34

The antiprogestin RU486 has been shown to inhibit the growth of a number of tumor cell lines and solid tumors which contain significant concentrations of progesterone receptor (PgR). It has been suggested that growth suppression may be due to a PgR-mediated cytotoxic effect. The R3327 HI prostatic carcinoma of the rat is considered to be a model for human prostatic carcinoma which has become resistant to androgen deprivation therapy. Since it is possible to induce high concentrations of PgR in this tumor with estrogen, it was of interest to investigate the possibility that RU486 could suppress its growth. Growth was assessed by tumor diameter, [3H]thymidine uptake and histopathological appearance after 2 or 8 weeks treatment with RU486 alone, diethylstilbestrol (DES) alone, and combined RU + DES treatment as compared with control animals. Tumor growth was not affected significantly by DES treatment alone. RU486 treatment alone suppressed PgR content and resulted in only insignificant inhibition of growth. However, when significant PgR concentrations were maintained by combined treatment with DES, RU486 significantly suppressed tumor growth (0.01 less than P less than 0.05 vs controls). This was accompanied by atrophy of the glandular epithelium. The results support the hypothesis that growth suppression may be brought about by a PgR-mediated mechanism. The data suggest that it may be possible to treat androgen-insensitive prostatic carcinoma by a new form of hormonal treatment.
J Steroid Biochem Mol Biol 1991 Nov
PMID:Suppression of the growth of the androgen-insensitive R3327 HI rat prostatic carcinoma by combined estrogen and antiprogestin treatment. 195 8

Activity of NAD-dependent 17 beta-hydroxysteroid dehydrogenase (E2DH), the enzyme which converts estradiol (E2) into its less active metabolite estrone (E1), has been previously characterized in normal human breast cells in culture and in benign and malignant breast tumors. E2DH activity is far greater in epithelial cells than in fibroblasts. Moreover, it is progesterone dependent in epithelial cells. It was therefore interesting to explore E2DH in the progesterone receptor (PR)-rich T47D cell line as a possible marker of hormone dependence in breast cancer cells. In T47D cells, transformation of [3H]E2 to E1 is limited. The metabolism seems to be preferentially oriented in the way E1----E2 in these cells. However, in the presence of the cofactor NAD the conversion of E2 into E1 increases. Moreover, treatment of T47D cells in culture by the progestin R5020 stimulates E2 to E1 conversion 2- to 3-fold. Stimulation of E2DH (E2----E1) activity reflects both the presence and the operability of PR. This observation underlines the possible interest of E2DH assay in parallel to estradiol receptor and PR to evaluate hormone-dependence of breast cancer.
J Steroid Biochem Mol Biol 1991 Nov
PMID:17 beta-estradiol dehydrogenase (E2DH) activity in T47D cells. 195 11


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