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747 records · Page 42Linked to original sources
PubMed1981

Feline mammary hypertrophy/fibroadenoma complex: clinical and hormonal aspects.

Abnormal mammary enlargement, characterized microscopically by hyperplasia of both epithelial and mesenchymal tissues, was studied in 26 cats which were mostly young, sexually intact females. Clinicopathologic data indicated that mammary hypertrophy was likely progesterone-dependent. Administration of progestins preceded this condition in 5 cats, 4 of which were neutered. Serum progesterone concentrations (6.7 ng/ml) were increased in 1 of the 3 cats tested. Estrogen receptors were not found in the cytosols or nuclei of mammary tissues in the 2 cats studied. However, there were convincing 4S [3H]progesterone or 5S [3H]R5020 binding peaks which were suppressible by nonlabeled progestins. Progesterone receptors were measured at 14.9 and 8.6 fm/mg of protein, respectively. The apparent influence of progesterone, whether present as exogenous therapy in the male or female or as endogenous steroid of ovarian origin, has thus been demonstrated directly and indirectly in cats with mammary hypertrophy.

Adenofibroma↗
PubMed1981

The effect of sodium molybdate on the cytoplasmic estrogen and progesterone receptors in human endometrial tissues.

We have investigated the effects of including 10 mM sodium molybdate in the buffers used for analysis of cytoplasmic estrogen and progesterone receptors of normal human proliferative endometrium and endometrial carcinoma. Sodium molybdate does not increase the steroid binding capacity of the receptors, but imparts stability to the steroid bound receptor; the steroid-bound receptors in molybdate treated cytosol sediment as distinct 8-9S moieties in sucrose gradients of low ionic strength in contrast to those in untreated cytosol which sediment mainly as 4S. We conclude that sodium molybdate is a useful reagent for the assay and isolation of estrogen and progesterone receptors of human endometrial tissues.

Adenocarcinoma↗
PubMed1993

Progesterone regulates the murine multidrug resistance mdr1b gene.

P-glycoprotein, the product of the multidrug resistance (mdr) gene family, is a major determinant in the development of resistance to a large number of cancer chemotherapeutic agents and is also expressed normally in a variety of mammalian tissues. In rodents during pregnancy, there is a dramatic overproduction of the mdr1b form of P-glycoprotein at the lumenal surface of the secretory epithelium of the gravid uterus. An expression vector, mdr1b-CAT, was constructed by fusion of this promoter region to a reporter gene, the bacterial chloramphenicol acetyltransferase (CAT) gene. R5020, a progesterone agonist, increased approximately 3-fold the expression of mdr1b-CAT when transfected into T47D cells, a cell line that constitutively expresses the progesterone receptor. A far greater response to R5020 was observed when the cells were co-transfected with an expression vector for the A form of the progesterone receptor, but not the B form. A series of 5'-deleted clones of the mdr1b-CAT construct indicated that the region of responsiveness was located in the first untranslated exon of the gene. Furthermore, sequences from the first exon were able to confer responsiveness to the non-responsive thymidine kinase-CAT vector. This study demonstrates that progesterone specifically regulates the activity of the mdr1b promoter and that this response is directed solely by the A form of the progesterone receptor.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Binding studies of RU486 in different Reuber hepatoma variants.

The synthetic steroid RU486, which displays antiprogestin and antiglucocorticoid properties in different systems, inhibits cell growth in dexamethasone-sensitive H56 cells containing glucocorticoid receptors, as well as in dexamethasone-resistant S-H56-125 cells displaying a very low level of dexamethasone binding. In order to better understand the mechanism of the antiproliferative effect, the binding of RU486 to these hepatoma cells was examined. Results revealed the presence of two different kinds of binding sites for RU486 in dexamethasone-sensitive H56 cells whereas only one type of site was detected in the dexamethasone-resistant cells. These peculiar sites were also recognized by cortivazol during competition experiments. Thus, it seems that S-H56-125 cells contain an altered glucocorticoid receptor that binds RU486 and cortivazol but virtually not dexamethasone. The ability of RU486 to inhibit the growth of dexamethasone-resistant cells suggests this steroid may be used to treat tumor cells that develop glucocorticoid resistance after long-term treatment.

Animals↗
PubMed1993

Antagonist-occupied human progesterone receptors bound to DNA are functionally switched to transcriptional agonists by cAMP.

When steroid hormone antagonists have inappropriate agonist effects, the clinical consequences are grave. Progesterone antagonists bind to two naturally occurring isoforms of human progesterone receptors (hPR), hPRB and the NH2-terminally truncated hPRA, and usually inhibit agonist-stimulated transcription. It is shown here that elevation of cAMP levels in a human breast cancer cell line leads to the functional reversal of progesterone antagonist action. While hPR occupied by the antagonists RU486 and ZK112993 are transcriptionally inactive, the antagonist-occupied receptors become strong activators of transcription in the presence of 8-Br-cAMP. However, this functional switch does not occur with the progesterone antagonist ZK98299, which, unlike RU486 and ZK112993, is unable to induce hPR binding to DNA. This suggests that the 8-Br-cAMP-induced transcriptional reversal requires that the antagonist-occupied receptors be bound to DNA. Even with agonist-occupied hPR, addition of 8-Br-cAMP results in a synergistic increase in transcriptional activity. When hPRA alone are transiently expressed in COS-1 cells, transcription of a reporter gene is stimulated by the agonist R5020 and by 8-Br-cAMP and is synergistic when both are present; but the 8-Br-cAMP-dependent component of transcription proceeds in the absence of hPRA, in the absence of the progesterone response element, and in the presence of a DNA-binding domain mutant of hPRA that cannot bind to the progesterone response element. Additionally, under the intracellular conditions in which 8-Br-cAMP activates antagonist-hPR complexes, there is no protein kinase A-mediated phosphorylation of the receptors. We discuss a model in which a gene that is independently transcribed by cAMP-responsive factors and by hPR can be selected for positive or negative regulation on the transcription complex due to additive or cooperative interactions between the two DNA-bound factors.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Potential mechanism of estrogen-mediated decrease in bone formation: estrogen increases production of inhibitory insulin-like growth factor-binding protein-4.

Using a recently developed human osteoblastic cell line (hFOB/ER9) with high levels (approximately 4,000 per nucleus) of estrogen receptors and the characteristic phenotype of the mature osteoblast, we tested the hypothesis that estrogen decreases bone formation by inhibiting the action of the insulin-like growth factor (IGF) paracrine/autocrine system. IGF-II, the predominant IGF produced by osteoblastic cells, was measurable in hFOB/ER9-conditioned medium (approximately 10 ng/mL) and its level did not change significantly after treatment with 17 beta-estradiol (E2) or anti-estrogens. Treatment with E2 at 0.1-100 nM decreased [3H]thymidine uptake to 53% of control (p < 0.001) in a dose-dependent fashion. The predominant IGF-binding proteins (IGFBPs) produced by hFOB/ER9 and by normal trabecular osteoblasts are IGFBP-3 and IGFBP-4, of which IGFBP-4 is consistently inhibitory of IGF action. Treatment with E2 at 0.01-10 nM for 48 h increased IGFBP-4 mRNA to 346% +/- 90% (mean +/- SE) of control (p < 0.05) and IGFBP-4 protein to 278% +/- 75% of control (p < 0.01) in a dose-dependent fashion but did not alter IGFBP-3 mRNA or protein. E2 treatment also attenuated IGF-dependent, IGFBP-4 specific proteolysis to approximately 50% of control. ICI 182,780, a pure anti-estrogen, completely blocked E2-mediated decreases in cell proliferation and increases in levels of IGFBP-4 mRNA and protein. Treatment of the hFOB/ER9 cells with recombinant human IGFBP-4 (200 ng/mL) decreased cell proliferation to 55% of control (p < 0.01). Thus, E2 acts on osteoblastic cells to increase availability of inhibitory IGFBP-4, by both increasing its production and decreasing its degradation, which may oppose the mitogenic effect of the IGFs on osteoblastic cells. This action may mediate, at least in part, the decreases in bone formation that are observed after estrogen treatment in vivo.

Antibodies↗