Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04155 (pS2)
 1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of immature 21-day-old female Sprague-Dawley rats with 17 beta-estradiol (E2) (0.5 microgram/rat) caused a significant increase in uterine wet weight, DNA synthesis, progesterone receptor (PR) binding, and peroxidase activity. At doses as high as 40 mg/rat, the bioflavonoid naringenin did not cause a significant increase in any of these E2-induced responses. However, in rats cotreated with E2 (0.5 microgram/rat) plus naringenin (30 mg/rat); there was a significant decrease in E2-induced uterine wet weight, DNA synthesis, PR binding, and peroxidase activity, indicating that naringenin exhibits antiestrogenic activity in the immature rodent uterus. The binding of uterine nuclear extracts to a 32P-labeled estrogen responsive element (ERE) or progesterone responsive element (PRE) was determined using gel electrophoretic band shift assays. Incubation of [32P]ERE with uterine nuclear extracts from rats treated with naringenin or E2 resulted in the formation of estrogen receptor (ER):ERE complexes; a higher mobility complex was prominent in the extracts from E2-treated rats, whereas a lower mobility complex was observed using nuclear extracts from naringenin-treated animals. There was a significant decrease in the intensity of the E2-induced complex using nuclear extracts from rats treated with E2 plus naringenin. In contrast, transformed cytosol from control rats gave an intense ER:ERE complex, whereas the intensity of the band was decreased markedly using transformed uterine cytosol from treated rats. Formation of a PR:PRE complex was also determined using transformed uterine cytosol. Cytosol from E2-treated rats gave an intense retarded band, whereas only weak bands were observed using cytosols from DMSO- (solvent), naringenin-, or naringenin plus E2-treated cells. The results of in vitro studies showed that 1 nM E2 increased (3- to 4-fold) the growth of MCF-7 human breast cancer cells, whereas 1-1000 nM naringenin had no effect on cell proliferation. In cells cotreated with 1 nM E2 plus 1000 nM naringenin, there was a significant decrease in E2-induced cell growth. In MCF-7 cells transiently transfected with a pS2 promoter-regulated luciferase reporter gene, naringenin exhibited weak estrogenic activity. In cells cotreated with 0.1 or 1.0 microM naringenin plus 1 nM E2, naringenin inhibited E2-induced luciferase activity. The results of these studies confirmed that naringenin is a weak estrogen that also exhibits partial antiestrogenic activity in the female rat uterus and MCF-7 human breast cancer cells.
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PMID:Naringenin: a weakly estrogenic bioflavonoid that exhibits antiestrogenic activity. 750

Antagonists of steroid hormones are clinically important in the management of breast cancer. However, the duration of response is limited due to the development of hormone-independent tumors in virtually all cases. In an attempt to obtain insight into the mechanisms underlying antiestrogen resistance, the consequences of epigenetic changes in gene expression were studied in vitro. Estrogen-dependent ZR-75-1 human breast cancer cells were treated with 5-azacytidine, an inhibitor of DNA methylation, and cultured in the absence of estradiol or in the presence of antiestrogens. Estrogen-independent cell colonies developed within 3 weeks at high frequency in 5-azacytidine-treated cultures (0.7 x 10(-3), in contrast to control cultures (< or = 10(-8). The derived cells (ZR/AZA) were resistant to 4-hydroxytamoxifen and ICI 164,384, independent of the selection protocol, but had lost the ability to grow anchorage-independent. Whereas expression of estrogen receptor, progesterone receptor, and pS2 were down-regulated, expression of epidermal growth factor (EGF) receptor and HER2/neu were increased in ZR/AZA cells. In contrast to the stable altered expression patterns of estrogen receptor and EGF receptor, transient keratin 7 expression was observed. Transforming growth factor-alpha mRNA was identified in ZR-75-1 cells and ZR/AZA cells and EGF-like peptides were secreted in the culture medium. Proliferation of ZR/AZA cells could be partially inhibited with an EGF receptor-blocking antibody. Presence of both growth factor receptors and possible ligands suggests the development of an autocrine growth mechanism. Our data show that epigenetic alterations of gene expression result in rapid progression of breast cancer cells to hormone independence.
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PMID:Induction of estrogen independence of ZR-75-1 human breast cancer cells by epigenetic alterations. 753 60

BRCA1 mRNA and protein levels are regulated by the steroid hormones estrogen and progesterone in human breast cancer cells. BRCA1 mRNA and protein levels were significantly decreased in estrogen-depleted MCF-7 and BT20T cells and increased again after stimulation with beta-estradiol. The increase in BRCA1 expression upon stimulation with estrogen was not coordinated with the early induction of the estrogen-dependent pS2 gene but closely paralleled the delayed increase in the S-phase dependent marker cyclin A. T47-D cells deprived of steroid hormones and subsequently stimulated with progesterone also showed a delayed increase in BRCA1 mRNA expression. However, no change in BRCA1 protein was detected in these cells. When considered together, the data suggest that steroid hormones may affect BRCA1 expression indirectly by altering the proliferative status of the cells rather than acting directly on DNA sequences in the BRCA1 gene itself.
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PMID:Hormone-dependent regulation of BRCA1 in human breast cancer cells. 755 29

For quantificative determination of ERBB2 gene amplification in archival human carcinoma specimens we have developed a rapid, non-radioactive approach, which is based on the differential polymerase chain reaction (PCR) and fluorescent DNA technique. Sequences from the ERBB2 gene and from a single-copy reference gene were amplified simultaneously by PCR, in which one of each primer pair was fluorescently labelled. PCR products were separated by polyacrylamide gel electrophoresis in an automated DNA sequencer and directly quantified after laser activation and emission scanning using appropriate software. This fluorescent differential polymerase chain reaction (fd-PCR) method was used for quantificative determination of ERBB2 gene amplification in 195 formalin-fixed, paraffin-embedded breast carcinoma tissues. ERBB2 gene amplification was found in 52 (26%) of these tumors and correlated significantly with tumor size, absence of estrogen receptor (ER) and pS2 expression, but not with absence of progesterone receptor (PR) or presence of epidermal growth factor receptor (EGF-R) expression, lymph-node metastases or grading. In univariate analysis, ERBB2 gene amplification showed no significant correlation with clinical outcome, either in the whole population or in the subgroup defined by positive axillary lymph-node metastases. However, within the node-negative subgroup, patients with ERBB2 gene amplification had significantly decreased relapse-free survival and overall survival (p < 0.05). The fd-PCR assay is a valuable tool for determination of amplification of ERBB2 gene as well as further oncogenes. In this way, more detailed information about individual tumor biology may be acquired by a routine assay.
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PMID:ERBB2 gene amplification detected by fluorescent differential polymerase chain reaction in paraffin-embedded breast carcinoma tissues. 759 Dec 99

The methylation status of the cytosines located on the 5' region of the pS2 gene have been investigated in two human breast cancer cell lines. The genomic sequencing method used is based on an oxydative deamination by NaHSO3 of the unmethylated cytosines, but not 5-methylcytosine. Data obtained indicate that in the DNA extracted from the pS2-expressing cell line, MCF7, the CpG located at the 5' flanking sequence of pS2 are unmethylated. In contrast in the non-expressing cell line, BT20, these CpG are largely methylated. However, this correlation is not observed at all CpG sites, since a significant portion of the cloned PCR fragments obtained from BT20 cells are unmethylated at specific CpG sites. These results suggest that the methylation status of only some of the CpG located at the 5' flanking sequences of pS2 might differ between expressing and nonexpressing cell lines.
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PMID:Genomic sequencing indicates a correlation between DNA hypomethylation in the 5' region of the pS2 gene and its expression in human breast cancer cell lines. 760 4

Paracrine interactions between breast-cancer cells (MCF7) and stromal fibroblasts were studied in relation to the presence of steroid hormones, using co-cultures in which the 2 populations were separated by a microporous membrane. Densities and DNA-synthesis rates of the co-existing populations were interrelated. Proliferation was, therefore, viewed as the cumulative result of several factors, some of which are non-specific, e.g., are density-dependent, and some are specifically related to the feeders' origin and/or to culture conditions. Specific effects were measured and evaluated by stepwise analysis of covariance. MCF7 stimulated proliferation of fibroblasts differentially. Malignant-tumour fibroblasts were stimulated more than non-pathological ones. The magnitude of these effects was dependent on the presence of steroids. A similar analytical method was used for evaluating differential stromal influences on 4 epithelial phenotypic characters commonly used as prognostic markers. The estrogen-receptor, progesterone-receptor, pS2 and cathepsine-D phenotypes of MCF7, as well as their interrelations, were dependent on the origin of the fibroblasts, i.e., embryonic or adult, normal or tumoral.
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PMID:Selective interactions between mammary epithelial cells and fibroblasts in co-culture. 792 27

A series of 201 bladder cancer biopsy specimens was analysed immunohistochemically for the expression of pS2 protein. Altogether, 61 per cent of the tumours were pS2-negative; in 16 per cent less than 1 per cent and in 23 per cent of cases more than 1 per cent of cells were pS2-positive. Normal transitional epithelium was negative for pS2. The fraction of positive cells was higher in poorly differentiated non-papillary tumours and in invasive tumours with pelvic lymph-node (P = 0.05) and distant metastasis (P = 0.10). pS2 expression was not related to sex, while patients aged 60-70 years had low fractions of pS2-positive cells (P = 0.03). DNA ploidy, S-phase fraction, mitotic index, morphometric nuclear features, and expression of c-erbB-2, p53, and epidermal growth factor receptor were independent of expression of pS2. Tumours expressing pS2 in over 10 per cent of cells had a lower survival probability (P = 0.0486). The results show that pS2 is expressed in 40 per cent of transitional cell bladder tumours, but that this marker has no clinical significance over established prognostic factors.
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PMID:Expression of pS2 protein in transitional cell bladder tumours. 796 92

Assignment of the 1H and 31P NMR spectra of a phosphorodithioate modified oligonucleotide decamer duplex, d(CGCTTpS2-AAGCG)2 (10-mer-S; a site of dithioate substitution is designated with the symbols pS2-), was achieved by two-dimensional homonuclear TOCSY, NOESY and 1H-31P Pure Absorption phase Constant time (PAC) heteronuclear correlation spectroscopy. In contrast to the parent palindromic decamer sequence (1) which has been shown to exist entirely in the duplex B-DNA conformation under comparable conditions (100 mM KCl), the dithiophosphate analogue forms a hairpin loop. However, the duplex form of the dithioate oligonucleotide can be stabilized at lower temperatures, higher salt and strand concentration. The solution structure of the decamer duplex was calculated by an iterative hybrid relaxation matrix method (MORASS) combined with 2D NOESY-distance restrained molecular dynamics. These backbone modified compounds, potentially attractive antisense oligonucleotide agents, are often assumed to possess similar structure as the parent nucleic acid complex. Importantly, the refined structure of the phosphorodithioate duplex shows a significant deviation from the parent unmodified, phosphoryl duplex. An overall bend and unwinding in the phosphorodithioate duplex is observed. The structural distortion of the phosphorodithioate duplex was confirmed by comparison of helicoidal parameters and groove dimensions. Especially, the helical twists of the phosphorodithioate decamer deviate significantly from the parent phosphoryl decamer. The minor groove width of phosphorodithioate duplex 10-mer-S varies between 8.4 and 13.3 A which is much wider than those of the parent phosphoryl decamer d(CGCTTAAGCG)2 (4.2 approximately 9.4 A). The larger minor groove width of 10-mer-S duplex contributes to the unwinding of the backbone and indicates that the duplex has an overall A-DNA-like conformation in the region surrounding the dithiophosphate modification.
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PMID:2D 1H and 31P NMR spectra and distorted A-DNA-like duplex structure of a phosphorodithioate oligonucleotide. 812 79

Most breast tumors show estrogen-dependent growth and are thus susceptible to antiestrogenic therapy. MCF-7 cells, obtained from a human estrogen-dependent breast carcinoma, are widely used for studying the modulation of estrogenic responses by different effectors. All-trans-retinoic acid (RA) and 1,25-dihydroxyvitamin D3 (Vit D3) inhibited estrogen-induced growth of MCF-7 cells and their effect was potentiated by the classical antiestrogen, hydroxytamoxifen. In MCF-7 cells, we found that RA and Vit D3 also inhibited estrogen-induced transcription; this was shown both for an endogenous gene (pS2) and for various exogenous transfected genes. Their inhibitory effect could not be reversed by increasing estradiol concentrations, showing that contrary to classical antiestrogens, they did not compete with estradiol to bind the estrogen receptor (ER). Analysis of the inhibitory mechanisms indicates that RA and Vit D3 receptors can directly or indirectly impair the binding of ER to the estrogen responsive element. The antagonist effect of RA would be found especially at DNA level since it seems to essentially involve an estrogen responsive element. The antagonist effect of Vit D3 would be found especially at the ER level since it seems to concern estrogen binding and dimerization domains of ER. We conclude that the antiestrogenic effects of RA and Vit D3 are similar since they can, via their receptors, interfere with estrogenic action at the estrogen responsive element level but that they are not identical since different molecular mechanisms are involved.
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PMID:Antiestrogenic effects of all-trans-retinoic acid and 1,25-dihydroxyvitamin D3 in breast cancer cells occur at the estrogen response element level but through different molecular mechanisms. 813 48

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exhibits a broad spectrum of antiestrogenic activities in rodents and mammalian cells in culture. The effects of TCDD on 17 beta-estradiol (E2)-induction of pS2, a prognostic marker for breast cancer, were investigated in MCF-7, ZR-75, HeLa, and Hepa 1c1c7 wild-type and mutant cells. These effects were compared to the suppressive activities of the congener, 2,8-dichlorodibenzo-p-dioxin, and the established antiestrogens, ICI 164,384 and tamoxifen, in order to determine the relative potency of TCDD and to distinguish the mechanism of action of Ah receptor-mediated antiestrogens. Treatment of MCF-7 cells with 10 nM TCDD decreased E2-induced secreted pS2 protein levels by 50% and the induction of the transiently transfected -1100 to -86 pS2 promoter-regulated reporter gene (pS2-LUC) by 57%. Comparable effects on PS2-LUC activity were observed in HeLa and ZR-75 cells. In contrast, TCDD had minimal effects on pS2ERE(-405 to -393)-LUC induction, whereas treatment with 10 nM ICI 164,384 caused a 60% decrease in luciferase activity. In Hepa 1c1c7 wild-type and clone 1 (C1) mutant cells, TCDD also reduced E2 induction of pS2-LUC activity but had little effect in clone 4 (C4) or clone 12 (C12) mutant cells. However, suppression was reestablished following transfection of the human Ah receptor nuclear translocator (ARNT) complementary DNA expression vector into C4 cells and the mouse Ah receptor (AhR) complementary DNA expression vector into C12 cells. Induction of pS2-LUC activity by the ligand-dependent and -independent chimeric estrogen receptors (HE15, HE19, ERcVP16, and ERGR) were also used to examine the role of E2 metabolism and the mechanism of TCDD-mediated antiestrogenic activity. Induction by HE15 and ERcVP16 was suppressed by 57 and 74%, respectively, following treatment with TCDD, whereas ICI 164,384 was significantly less effective (38 and 20%, respectively). These results demonstrate a role for the Ah receptor in TCDD-mediated suppression of E2-induced pS2 expression. Data is presented demonstrating that the effect requires sequences within the pS2 promoter other than the estrogen response element and is independent of E2 oxidative metabolism.
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PMID:Antiestrogenic effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on 17 beta-estradiol-induced pS2 expression. 816 1


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