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)

The catecholestrogens, namely 2-hydroxyestradiol (2-OH-E2) and 4-hydroxyestradiol (4-OH-E2) are important, naturally occurring metabolites of E2. Here we studied their role on estrogen dependent processes. Using the MCF-7 cell line as a model system we analyzed the potency of 2- and 4-OH-E2 on the synthesis of the 160 kDa secreted protein and on the transcription of the pS2 mRNA. Both processes are known to be E2 inducible and are mediated by the estrogen receptor. Control incubations using E2 and antiestrogens were performed to validate the assay procedure and to enable us to comparatively study the effects of the catecholestrogens. Stimulating MCF-7 cells for 2 days with 10(-8) M 2- or 4-OH-E2 resulted in an induction of the synthesis of the 160 kDa protein and in an increase in pS2 mRNA. Following hormonal stimulation with 2- or 4-OH-E2 [35S]methionine labeling of MCF-7 cells increased the level of newly synthesized and secreted 160 kDa protein 54 and 88% compared with the inductive potency of E2 (100%). The pS2 mRNA in MCF-7 cells was increased by a 2 day treatment with 10(-8) M 2- or 4-OH-E2 by 48 and 79%, respectively, compared to E2. Therefore, we conclude that the estrogen receptor is transcriptionally active in MCF-7 cells upon binding of catecholestrogens. The estrogen receptor in vivo may be active if the intracellular concentration of catecholestrogens generated is sufficient to allow occupation of the receptor. The possible action of these hormones in vivo is discussed.
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PMID:Catecholestrogens are agonists of estrogen receptor dependent gene expression in MCF-7 cells. 818 Jan 6

The effects of cadmium on estrogen receptor and other estrogen-regulated genes in the human breast cancer cell line MCF-7 were studied. Treatment of MCF-7 cells with 1 microM cadmium decreased the level of estrogen receptor 58%. Cadmium induced a parallel decrease in estrogen receptor mRNA (62%). Progesterone receptor levels increased 3.2-fold after cadmium treatment. This induction was blocked by the anti-estrogen ICI-164,384. Progesterone receptor mRNA was also increased by cadmium, as well as cathepsin D mRNA. An in vitro nuclear transcription run-on assay showed that cadmium increased the transcription of the progesterone receptor and pS2 genes and decreased transcription of the estrogen receptor gene. These are not general effects of heavy metals, as zinc, 25 and 100 microM, did not affect progesterone receptor protein and mRNA levels. Cadmium stimulated pS2 and progesterone receptor mRNAs in a clone of MDA-MB-231 cells transfected with the human estrogen receptor, but had no effect in MDA-MB-231 cells transfected with antisense estrogen receptor. Cadmium also stimulated an estrogen response element in transient transfection experiments. These data suggest that the effects of cadmium are mediated by the estrogen receptor independent of estradiol. In addition to its effect on gene expression, cadmium induced the growth of MCF-7 cells 5.6-fold.
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PMID:Effect of cadmium on estrogen receptor levels and estrogen-induced responses in human breast cancer cells. 820 12

A third of breast cancers are estrogen dependent and respond to endocrine therapy. The estrogen receptor (ER) was the first marker used to predict the responses to treatment, and two-thirds of ER positive tumors show a favourable response. Several estrogen-regulated proteins were further studied in a search to enhance the prediction accuracy of ER status: progesterone receptors, 24-K heat shock protein, cathepsin D, and recently pS2 protein. The pS2 gene, also named BCEI, pNR-2 [4], Md2, was first identified by two groups using differential screening of a complementary DNA library derived from a human breast carcinoma cell line (MCF-7) grown with and without estrogens. Later on two independent English groups and a Japanese group identified a gene similar to pS2. The pS2 mRNA, relatively abundant (0.8%) in the MCF-7 cell line when stimulated by estrogens, encodes a cystein-rich, 84 aminoacids peptide which is secreted by breast cancer cells. The expression of the pS2 gene, pS2 protein assays in tumor cytosols and more recently pS2 detection by immunocytochemistry, have been described in several series of breast cancers.
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PMID:Clinical significance of the estrogen regulated pS2 protein in mammary tumors. 824 Jul 4

DNA-protein interactions around the regulatory region of the pS2 gene were studied to gain insight into the mechanisms that operate in the estrogen receptor regulated expression of this gene in the MCF-7 human breast cancer cell. Using a revised photocrosslinking technology in combination with gel retardation assays, two distinct multiprotein DNA complexes were shown to assemble in an estrogen receptor-dependent process. Immunological analysis demonstrated the participation of both the estrogen receptor and a c-fos related protein in the formation of these complexes. The results support a model of estrogen receptor function in which the receptor facilitates the formation of multiprotein complexes at DNA sites that can regulate the transcription of a hormone responsive gene by RNA polymerase II and any additional general transcription machinery. These receptor-containing complexes are referred to as "receptorsomes."
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PMID:Estrogen receptor-dependent formation of two distinct multiprotein complexes on the human pS2 gene regulatory segment. Participation of a c-fos related protein. 825 52

Epidemiological studies suggest a lowered risk of hormone-dependent cancers among vegetarians, but the basis for this association remains unclear. Vegetables and fruits contain certain compounds which can be converted to biologically active hormone-like substances, such as lignans and isoflavones, by intestinal flora. The interaction of these compounds with endogenous hormones may be a novel, diet-dependent mechanism in cancer prevention. To explore this possibility, we developed a rapid, specific assay system to screen for compounds with estrogen-like activity in tissue culture. We utilized the estrogen receptor-positive breast cancer cell MCF-7 and monitored the expression of the estrogen-responsive protein pS2 by Northern blots. Our results indicated that the phenolic compounds daidzein, equol, nordihydroguaiaretic acid, enterolactone, and kaempferol were able to elicit an estrogen-like response, while quercetin and enterodiol were not.
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PMID:Stimulation of pS2 expression by diet-derived compounds. 831 86

In MCF7 human breast cancer cells, the antiestrogens 4-hydroxy-tamoxifen and ICI 164,384 inhibit the mitogenic activity of epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). These growth factors also stimulate the expression of cathepsin-D and pS2 genes. Therefore, we studied the effects of antiestrogens on growth factor induction of pS2 and cathepsin-D mRNA. The two antiestrogens strongly inhibited the transcriptional induction of pS2 by growth factors. On the contrary, estradiol and IGF-I or EGF had an additive effect on pS2 mRNA accumulation. Growth factor induction of cathepsin-D was also inhibited by ICI 164,384. By contrast, 4-hydroxytamoxifen had an agonist effect on cathepsin-D and an additive effect on IGF-I-induced mRNA. When 12-O-tetradecanoylphorbol-13-acetate or 8-bromo-cAMP (8-Br-cAMP) was used instead of growth factors, similar effects of 4-hydroxytamoxifen and ICI 164,384 were obtained on pS2 (12-O-tetradecanoylphorbol-13-acetate and 8-Br-cAMP) and cathepsin-D (8-Br-cAMP) induction. A mechanism based on the classical competitive inhibition by antiestrogens of estrogen binding and action on the estrogen receptor was very unlikely, as 1) no antigrowth factor activity was obtained with R5020, which was a potent inhibitor of estrogen induction of pS2 and cathepsin-D mRNA; 2) in the Ishikawa endometrial cancer cell line, the cathepsin-D gene is unresponsive to estrogen, but was inhibited by antiestrogen after its induction by EGF or 8-Br-cAMP; and 3) the residual estrogen concentration in cells was too low to induce the expression of estrogen-specific genes. However, antiestrogens did not inhibit the expression of all genes induced by growth factors, as they were without effect on IGF-I induction of glyceraldehyde-3-phosphate dehydrogenase mRNA. These results demonstrate that antiestrogens can modulate the transcription of some growth factor-induced genes and strongly suggest that this effect is not due to interference with residual estrogens.
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PMID:Synthetic antiestrogens modulate induction of pS2 and cathepsin-D messenger ribonucleic acid by growth factors and adenosine 3',5'-monophosphate in MCF7 cells. 834 99

A new complementary DNA, p27, has been cloned and sequenced from estradiol-treated MCF7 human breast carcinoma cells. It encodes a putative highly hydrophobic protein of 122 amino acids which has a 33% overall sequence similarity to the product of the 6-16 gene (R. L. Friedman, S. P. Manly, M. McMahon, I. M. Kerr, and G. R. Stark, Cell, 38: 745-755, 1984), which is transcriptionally induced by interferons of the alpha/beta type. We demonstrate here that the p27 gene, which is located in band q32 of human chromosome 14, is also induced by interferon-alpha in human cell lines of different origin and that expression is independent of the presence of estradiol receptor in the cells. High levels of p27 RNA were found in vivo in approximately 50% of primary human breast carcinomas (21 were tested by Northern blotting). In situ hybridization to some of the p27-overexpressing tumors showed that the p27 RNA is localized in cancer cells and sometimes also in fibroblastic cells of tumor stroma. p27 RNA levels in the tumors did not correlate with the presence of estrogen receptor or with the expression of the estrogen-induced pS2 gene. Further studies are now necessary to elucidate the cause of p27 gene overexpression in breast carcinoma and in particular to determine whether it corresponds to chromosomal rearrangements in the 14q32 region and/or to induction by interferons of the alpha/beta type.
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PMID:Identification of a new interferon-alpha-inducible gene (p27) on human chromosome 14q32 and its expression in breast carcinoma. 835 38

A hormone-independent but hormone-responsive subpopulation (MCF7/MIII) of the hormone-dependent MCF-7 human breast cancer cell line (R. Clarke et al., Proc. Natl. Acad. Sci. USA 86: 3649-3653, 1989) was further passaged in ovariectomized nude mice and re-established in vitro as the continuous cell line MCF7/LCC1. The lag time to the appearance of proliferating tumors in ovariectomized animals is significantly reduced in MCF7/LCC1 when compared with MCF7/MIII cells. In gel denaturation/renaturation analysis of tumor, genomic DNA does not reveal significant differences in the pattern of detectable DNA amplifications between parent MCF-7 cells and MCF7/LCC1 cells. In the absence of estrogen, steady-state levels of phosphoinositol turnover are similar in both MCF-7 and MCF7/LCC1 cells, but turnover is increased by estrogen only in MCF-7 cells. MCF7/MIII and MCF7/LCC1, but not MCF-7 cells, express a high baseline level of the estrogen-regulated pS2 mRNA. The baseline level of expression of progesterone receptor protein, but not mRNA, is higher in MCF7/LCC1 when compared with either MCF-7 or early passage MCF7/MIII cells. However, while the estrogen receptor is also an estrogen-regulated gene, MCF7/MIII and MCF7/LCC1 cells retain estrogen receptor levels equivalent to the parental MCF-7 cells. These data indicate that progression to hormone independence can occur without major gene amplifications or a high constitutive induction of phosphoinositide metabolism. Thus, DNA amplifications may be acquired during the early initiation and/or promotional events of carcinogenesis. Significantly, acquisition of a hormone-independent but responsive phenotype in human breast cancer is associated with perturbations in the expression of specific estrogen-regulated genes.
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PMID:Acquisition of hormone-independent growth in MCF-7 cells is accompanied by increased expression of estrogen-regulated genes but without detectable DNA amplifications. 838 Feb 54

The expression of pS2 was examined histochemically in paraffin sections taken from biopsy material from patients diagnosed with ductal carcinoma in situ (DCIS). Often intense immunoreactivity, to an anti-pS2 monoclonal antibody, was observed in comedo, solid, cribriform and micropapillary types of DCIS, with significant positivity found in 63-67% of cases. In 15 samples analysed, we found a good correlation between pS2 expression and presence of progesterone receptor positive cells, but not with estrogen receptor. There was only a limited degree of correspondence between the cells staining with these anti-sera. Some pS2 positive cells were also seen in normal acini in areas adjacent to cancer but much less frequently in sections of normal breast from reduction mammoplasty. Most normal areas were negative, as were cysts. In benign proliferative conditions (seen in sections with and without DCIS) such as adenosis, sclerosing adenosis, mild and florid ductal epithelial hyperplasia, significant pS2 positivity was seen in about 50% of cases. These results suggest that there is a progressive increase in pS2 from normal to benign to cancer cells and that this gene is expressed in both the invasive and pre-invasive forms of breast cancer.
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PMID:Immunohistochemical localisation of pS2 protein in ductal carcinoma in situ and benign lesions of the breast. 838 77

This study examined whether levels of estrogen receptor (ER), progesterone receptor (PR), and expression of estrogen regulated pS2 and/or heat shock protein (hsp) 27 were associated with drug resistance in a series of MCF-7 sublines expressing modest (i.e. 3- to 14-fold), yet clinically relevant, levels of resistance to vincristine (VCR). These sublines were variously derived following pulsed exposures to VCR, to fractionated X-irradiation, or to alternating drug and X-ray treatments. This selection procedure more closely reflects the clinical treatment of breast tumors than the use of continuous drug exposures. The drug-selected sublines exhibited the classical multidrug resistance phenotype (MDR) characterized by cross-resistance to vinblastine (VLB), etoposide (VP-16), and Adriamycin (ADR), overexpression of P-glycoprotein (Pgp), impaired accumulation of [3H]-VCR and of Rhodamine-123 (Rh 123), and altered activities of certain drug detoxification enzymes. This classic MDR phenotype was associated with a lack of mitogenic response to estrogen or antiestrogen, related to loss of detectable ER and PR; consistent with these data, neither pS2 nor hsp27 expression was detectable. In contrast, X-ray-pretreated VCR-resistant cells (MCF/DXR-10) cells exhibited a distinctive resistance phenotype proving cross-resistant to VLB and VP-16 but not to ADR, and Pgp overexpression was not detectable. Furthermore, these VCR-resistant DXR-10 cells retained parental levels of ER and PR, exhibited sensitivity to estrogen and 4-hydroxytamoxifen, and expressed detectable levels of pS2 and hsp27. Comparable characteristics to these MCF-7/DXR-10 cells were also identified in a similarly-derived X-ray-pretreated VCR-resistant subline of the ZR-75-1 human breast tumor cell line. These data therefore indicate that functional ER are frequently, but not invariably, modified in tumor cells which express resistance to multiple drugs.
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PMID:Differential expression of steroid receptors, hsp27, and pS2 in a series of drug resistant human breast tumor cell lines derived following exposure to antitumor drugs or to fractionated X-irradiation. 840 Mar 21


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