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At least 199 records · Page 11Linked to original sources
PubMed1981

Androphilic proteins in the human prostate.

Dihydrotestosterone-binding protein in cytosols from human prostates was different from the R1881- and R5020-binding proteins. The R1881- and R5020-binding proteins in the cytosol were very similar and most of the binding sites for R1881 were capable of binding R5020. However, nuclear extracts showed equal binding to dihydrotestosterone and R1881, but not to R5020, suggesting that there might not be a progestin receptor in the human prostate. Maximum binding sites to dihydrotestosterone, R1881, and R5020 in cytosols were very similar among "normal" and pathological prostates except that dihydrotestosterone binding was higher in "normal" prostates than in the pathological ones. Histochemically, R1881-binding was observed in the epithelial cells and in malignant cells, but not in the stroma.

Androgen-Binding Protein↗
PubMed1984

Single case report of prostate adenocarcinoma in a dog castrated three months previously. Morphological, biochemical, and endocrine determinations.

During the course of another investigation, three dogs had been castrated 3 months previously. Upon completion of the experiment, it was discovered that one dog presented a spontaneous prostatic adenocarcinoma of intraalveolar proliferative type at histology. Prostate weight of this dog before castration was estimated to be 22 g by tridimensional measurement at laparotomy and remained relatively constant (19 g) 3 months after castration. These results indicate that if regression had occurred in some cell populations (androgen-dependent) it was only partial and masked by growth of androgen-independent cells. Analysis of 12 individual steroids in peripheral blood and in prostatic tissue attested of a normal adrenal secretory activity. A series of 15 hydrolytic enzymes along with receptors for androgen, estrogen, and progesterone, were determined in prostatic tissue obtained at sacrifice. Enzymatic activities were those of typical epithelial cells, and most of them remained relatively high despite low levels of circulating testosterone. However, two markers of androgen action in dog prostate, acid phosphatase and arginine esterase, were significantly reduced. Receptor levels were similar to those of castrated animals. Thus, cancer cells had probably retained some androgen sensitivity.

Adenocarcinoma↗
PubMed1986

Characterization of steroid receptors in human prostate using mibolerone.

Accurate quantitation of androgen receptors requires a radioactive ligand which has affinity and specificity for the receptor and which is stable to metabolic enzymes. In this report, we have characterized the properties of 7 alpha,17 alpha-dimethyl-17 beta-hydroxy-4-estren-3-one (mibolerone) in human benign hyperplastic prostate cytosol and compared them to those of 17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-trien-3-one (R1881). Mibolerone was found to have an affinity (Kd = 1.5 nM) greater than R1881. (Kd = 2.3 nM) for the androgen receptor in human prostate tissue. Surprisingly, mibolerone was found to bind with high affinity to the progesterone receptor in both human prostate (Kd = 5.9 nM) and rabbit uterus (Kd = 1.1 nM). However, binding to this receptor in both species could be blocked with a 500-fold excess of triamcinolone acetonide. [3H]Mibolerone binding to the androgen receptor was competed effectively with unlabeled dihydrotestosterone, R1881, and mibolerone but not by progesterone, diethylstilbestrol or R5020, in the presence of triamcinolone acetonide. Interestingly, mibolerone was more resistant to metabolism than R1881 in prostate cytosol when exposed to elevated temperatures (30 degrees C) for extended periods of time. However, when exposed to high-intensity ultraviolet irradiation, both compounds lost 50% of their binding ability in about 30 minutes. Mibolerone was found to have a very low affinity (Ki = 540 nM) for human sex steroid binding protein. These studies demonstrate that mibolerone is a useful ligand for androgen receptor assays. They also emphasize the need for including competitors of progesterone receptor binding in assays utilizing this steroid for androgen receptor measurements.

Animals↗
PubMed1993

Evidence for progesterone receptors in human osteoblast-like cells.

We report on the presence of progesterone receptor and its mRNA in a human osteoblast-like cell line (HOS TE85) using recombinant DNA methods, saturation analysis, specific immunoprecipitation with an anti-progesterone receptor antibody, and Northern blot analysis. These osteoblast-like cells were also found to be responsive to progesterone in a dose-dependent fashion through an augmentation in cellular alkaline phosphatase activity. These results support the presence of progesterone receptors in bone cells and suggest a direct effort of progesterone and/or antiprogestins on osteoblast cell function.

Alkaline Phosphatase↗
PubMed1993

Threonine on amino acid position 868 in the human androgen receptor is essential for androgen binding specificity and functional activity.

The human androgen receptor gene in the androgen sensitive prostate tumor cell line (LNCaP) contains a point mutation in codon 868 resulting in the substitution of threonine by alanine. This amino acid change is responsible for the increased affinity of the mutant receptor protein for progestagens and estrogens. To further elucidate the role of threonine 868 on androgen binding capacity, specificity and functional activity, threonine 868 was substituted by six different amino acid residues. Substitution by aspartic acid, lysine or tyrosine totally eliminated androgen binding and the mutated androgen receptors did not have any transcriptional activating potential with either R1881, R5020 or estradiol. Introduction of a serine or an alanine broadened the steroid specificity, as did the introduction of a cysteine to a lesser degree. It is concluded that threonine on position 868 of the human androgen receptor limits the ligand specificity of the receptor to androgens.

Amino Acid Sequence↗
PubMed1997

Progesterone binding to plasma membrane and cytosol receptors in the amphibian oocyte.

We have found a single class of progesterone binding sites at the amphibian oocyte plasma membrane, whereas two progesterone receptor forms, similar to those in chick and human, are present in the cytosol. In this study both plasma membranes and 105,000 x g cytosol from Rana pipiens oocytes were photoaffinity labeled with the synthetic progestin [3H]R5020. SDS-polyacrylamide gel electrophoresis of the photolabeled proteins in the oocyte cytosol indicate that the two forms have molecular weights essentially identical to that found for human breast tissue and chick oviduct, i.e., 80 and 110 kDa, and that the forms were present in approximately equimolar ratios. In contrast, the plasma membrane form is present as a single 110 kDa species and accounts for at least 50% of the total 110 kDa species. The presence of large amounts of the 110 kDa protein in both membrane and cytosol suggests that the plasma membrane receptor may not be unique, and that the 110 kDa form may function both in membrane and cytosol and/or that part of the cytosolic 110 kDa form represents progesterone receptor in the process of being transported to or from the plasma membrane.

Animals↗
PubMed1997

Heterogeneity of binding sites and bioeffects of raloxifene on the human leukemic cell line FLG 29.1.

The benzothiophene divarative raloxifene is known to mimic estrogen in human bone remodeling. To investigate the "in vitro" properties of raloxifene on osteoclast precursors, the human leukemic cell line FLG 29.1, which differentiates toward the osteoclastic phenotype, was examined for raloxifene binding and for evidence of its bioeffects. Scatchard and Hill analysis of binding data with the tritiated raloxifene demonstrated the presence of two classes of binding sites in both nuclear and cytosol fractions with Kd values of approximately 1 nM and approximately 5 nM, respectively. In addition, analysis of binding data using tritiated 17 beta E2 as ligand at high concentrations (10-40 nM) and either unlabeled 17 beta E2 or raloxifene as competitors gave similar results demonstrating the presence of type II EBS in these cells. Picomolar concentrations of raloxifene significantly (p < 0.05) inhibited cell proliferation. Moreover, the compound at nanomolar concentrations induced a significant dose- and time-dependent increase of progesterone receptor, and activated apoptotic cell death. These findings clearly demonstrate that raloxifene acts as an estrogen agonist in FLG 29.1 cells, acting through the estrogen receptor and, possibly, via multiple cooperative binding component(s).

Apoptosis↗
PubMed1993

Expression of 67 kDa laminin receptor in human breast cancer cells: regulation by progestins.

The level of 67 kDa laminin receptor (67LR) expression on breast and colon tumor cell surfaces was previously shown to be correlated with the capacity of tumor cells to metastasize. In the present work we investigate the effects of progestins and estrogen on the expression of 67LR in two sublines of the T47D human breast cancer cells: weakly tumorigenic, poorly invasive parental T47D cells and a highly tumorigenic, more invasive T47Dco subclone. Immunoblotting with an affinity purified antibody directed against a synthetic peptide recognizes the 67LR in these cells. 67LR expression in the T47Dco subclone is 5.5-fold higher than in their parental T47D cells. Treatment of T47D cells with 1 nM of the synthetic progestin R5020 results in a 4-fold increase in 67LR protein expression. Estrogen also induced 67LR expression, but only by 1.5-fold. The progestin-stimulated expression of the 67LR correlates with a 4.3-fold increase in attachment of T47D cells to laminin. A monoclonal antibody, mAb 13, directed against beta 1 integrin, completely blocks the attachment of T47D cells to fibronectin, only partially inhibits the attachment of T47D cells to laminin, and appears not to affect the progestin-stimulated laminin attachment of T47D cells. A new antiprogestin, ZK 112.993, significantly inhibits both progestin-stimulated 67LR expression and the increased attachment to laminin. These results suggest a possible role for progestin in mediating one of the multiple events thought to be important in metastasis of steroid receptor positive human breast cancer cells.

Analysis of Variance↗
PubMed1991

Immunoanalysis of calf uterine progesterone receptor: modulation of receptor-associated 90 kDa heat-shock protein. f.

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.

Animals↗
PubMed1992

Characterization by photoaffinity labeling of a steroid binding protein in rat liver plasma membrane.

The mechanism of steroid uptake by the cell remains controversial. [3H]R5020 was utilized to characterize by photoaffinity labeling the steroid binding site in plasma membrane. This binding was saturable, reversible and had one type of binding site (Kd = 33 +/- 4 nM, Bmax = 32 +/- 2 pmol/mg). [3H]R5020 could be prevented from binding by a variety of steroids (cortisol, progesterone, deoxycorticosterone, and levonorgestrel); estradiol did not have affinity for this binding site. The kinetics of R5020 photoactivation was time dependent and saturable. SDS-PAGE showed a specific band which corresponded to a 53-kDa peptide. The sucrose density gradient analysis has revealed the existence of a protein with a sedimentation coefficient of 3.6 +/- 0.2 S. This polypeptide shows different characteristics than cytosolic steroid receptor or serum steroid binding proteins. This binding protein could correspond to the steroid binding site previously found in the plasma membrane.

Affinity Labels↗
PubMed1980

Autoradiographic studies on the fetal and newborn uteri of the guinea pig after injection of 3H-progesterone into non-treated and into estradiol-primed animals.

The localization and retention of radioactivity in the uteri of fetal and newborn guinea pigs was studied after subcutaneous injection of 3H-progesterone into intact and estradiol-primed animals. In the fetal uterus of the animals treated with estradiol, a significant increase in the accumulation of silver grains was observed, mainly localized in the stroma and myometrium, but very little is detected in the uterine gland. On the other hand, in the uteri of newborns, the effect of estradiol on radioactivity retention was significantly less intense and the radioactivity is mainly localized in the epithelium and the uterine gland. These data correlate well with the quantitative evaluation of the concentration of progesterone-specific-binding sites in the non-treated and in the estradiol-primed fetal and newborn guinea pigs.

Animals↗
PubMed1987

Difference between R5020 and the antiprogestin RU486 in antiproliferative effects on human breast cancer cells.

We have compared the effects of the progestin R5020 and the antiprogestin RU486 on the growth of the MCF-7 and T47D breast cancer cell lines. Differences between the two compounds were demonstrated in several parameters. 1. Estradiol was required for the efficient inhibition of cell growth of both lines by R5020 but not by RU486. Therefore in the total absence of estrogen (phenol-red free medium), the effects of the two drugs on cell growth were dissociated, RU486 remaining inhibitory while R5020 was inactive. 2. The proteins secreted by cells were differently affected, since R5020 induced a 48K protein and decreased the production of the estrogen-regulated 52K protein, while RU486 had no effect on these two parameters. 3. The morphology of cells treated by R5020 was more altered in the presence of estradiol than in its absence, while that of cells treated by RU486 was not affected whether or not estradiol was present. 4. There was a greater reduction of estrogen receptor sites in MCF-7 cells produced by R5020 than by RU486. Even though the two drugs appear to act through the same progesterone receptor and to inhibit total protein secretion, it is likely that they exert their antiproliferative effects on cultured breast cancer cells by different mechanisms. R5020 antagonizes the stimulation produced by estradiol. RU486 by contrast exerts a more direct progesterone receptor mediated inhibitory effect requiring no synergism by estradiol and therefore does not act through a partial progestin activity.

Breast Neoplasms↗
PubMed1986

Antiestrogen action of progesterone in breast tissue.

In normal breast, estrogen stimulates growth of the ductal system, while lobular development depends on progesterone. Thus, estrogen and progesterone, when secreted in an adequate balance, permit the complete and proper development of the mammary gland. Progesterone may also have an antagonistic activity against estradiol, mediated through a decrease in the replenishment of the estrogen receptor, and also through increased 17 beta-hydroxysteroid dehydrogenase which leads to accelerated metabolism of estradiol to estrone in the target organ. Thus, it can be inferred that long periods of luteal phase defect leading to an unopposed estrogen effect on the breast might promote breast carcinogenesis.

17-Hydroxysteroid Dehydrogenases↗
PubMed1986

Adrenal steroids stimulate growth and progesterone receptor levels in rat uterus and DMBA-induced mammary tumors.

We have studied the effect of treatment with the adrenal steroids androst-5-ene-3 beta,17 beta-diol (delta 5-diol) and dehydroepiandrosterone (DHEA) on the growth and progesterone receptor levels of dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in the rat. While the total number of tumors in ovariectomized animals was 0.60 +/- 0.19 tumor per rat after 24 days, it increased to 2.54 +/- 0.50 (p less than 0.01) and 1.42 +/- 0.26 (p less than 0.01) in the delta 5-diol and DHEA (2 mg, twice daily) treated animals, respectively. While very few new tumors developed during a 24-day period in ovariectomized animals (0.07 +/- 0.07/rat), an average of 0.47 +/- 0.19 (p less than 0.05) new tumor per animal appeared in intact rats. In ovariectomized animals treated with delta 5-diol or DHEA, the numbers of new tumors were 0.77 +/- 0.26 (p less than 0.05) and 0.42 +/- 0.15 (p less than 0.05), respectively. An even more striking effect was observed on average total tumor area, which decreased from 4.70 +/- 0.95 cm2 in intact animals to 0.75 +/- 0.27 cm2 (p less than 0.01) following ovariectomy. Values of 9.79 +/- 2.25 (p less than 0.01) and 3.93 +/- 0.86 cm2 (p less than 0.01) were found in the delta 5-diol- and DHEA-treated ovariectomized animals, respectively. Treatment of ovariectomized animals with delta 5-diol and DHEA caused a marked increase (p less than 0.01) in progesterone receptor levels in both the uteri and DMBA-induced mammary tumors. Uterine weight was also stimulated (p less than 0.01) by treatment with the two adrenal steroids.(ABSTRACT TRUNCATED AT 250 WORDS)

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Inhibition of T47D human breast cancer cell growth by the synthetic progestin R5020: effects of serum, estradiol, insulin, and EGF.

The mechanism of the antiproliferative effects of progestins on human breast cancer cells is not known. In view of the ability of estrogen to stimulate human breast cancer cell production of peptide growth factors, and since previous studies have suggested that the inhibitory action of progestins is dependent on estrogen-stimulated growth, the present study examined the interaction of growth factors and the synthetic progestin R5020 on the proliferation of T47D human breast cancer cells. In this study, the concentrations of estradiol, insulin, and EGF for optimal stimulation of T47D cell growth in 3% dextran-charcoal treated fetal bovine serum (DCC-FBS) were determined to be 1 nM, 100 nM, and 1 nM, respectively. Furthermore, incubation with these optimal concentrations of estradiol, insulin, and EGF in various combinations produced additive effects on T47D cell proliferation, suggesting that these agents act, at least in part, by different mechanisms. In contrast, in a chemically defined medium (DM), both estradiol and EGF were unable to stimulate T47D cell proliferation. In the case of estradiol, the inability to demonstrate stimulation of T47D cell growth in DM was not due to down-regulation of the estrogen receptor. R5020 inhibited the growth of T47D cells, although its effect was more marked in the presence of 3% DCC-FBS than in DM. Stimulation of T47D cell growth by either estradiol or insulin in 3% DCC-FBS was effectively inhibited by R5020. In contrast, growth of T47D cells stimulated by EGF in the absence of estradiol was not markedly inhibited by R5020, the growth being comparable to that of untreated control cells. These findings suggest that the inhibitory effect of R5020 on T47D cell proliferation is dominant over the action of some, but not all, breast cancer mitogens.

Animals↗