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)

Two variants of the human estrogen-responsive breast cancer cell line MCF-7, were utilized to study the expression of an estrogen-induced gene, pS2, and an estrogen-induced Mr 52,000 protein. One variant cell line, I13, is growth inhibited after chronic exposure to estrogen. Both the pS2 gene product and the Mr 52,000 protein were produced at maximal levels at a time when I13 growth was inhibited by estrogen. The variant cell line, LY2, selected for its resistance to the growth-inhibitory effects of the antiestrogen, LY117018, grew normally in the presence of this drug, although both pS2 expression and Mr 52,000 protein production were inhibited. These results confirm that the pS2 gene and Mr 52,000 protein are estrogen-regulated elements, but the lack of correlation between their activities and variant cell growth suggests that they are not major autocrine growth-stimulatory agents.
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PMID:Use of two MCF-7 cell variants to evaluate the growth regulatory potential of estrogen-induced products. 394 73

We present the complete sequence of an mRNA which is induced by estrogen in the human breast cancer cell line MCF-7 [pS2 mRNA, Masiakowski et al., Nucleic Acids Res. 10, 7895-7903 (1982)]. Primer extension and cloning of double-stranded cDNA (ds-cDNA) into a vector designed to make full-length cDNA were used to determine the sequence of the fifteen 5'-terminal nucleotides which were not present in the original pS2 ds-cDNA clone. The mRNA sequence has a major open reading frame encoding 84 amino-acids, flanked by a 40 nucleotide 5'-untranslated region and a 198 nucleotide 3'-untranslated region preceding the polyA tail. The 3'-untranslated region contains a polyadenylation signal, AUUAAA, 14 nucleotides upstream from the polyA tail. The derived protein sequence contains a putative signal peptide region suggesting that the protein may be secreted. The nucleotide and derived amino-acid sequences were compared to previously determined sequences, particularly to those of hormone-regulated proteins and growth factors, and no obvious similarities were observed.
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PMID:Sequence of the pS2 mRNA induced by estrogen in the human breast cancer cell line MCF-7. 632 30

The effects of estradiol and antiestrogens on two estrogen-regulated proteins (52 and 160 kDa) and an estrogen-inducible mRNA (pS2) have been measured in the MCF7 human breast cancer cell line and two tamoxifen-resistant sublines. In MCF7 cells, tamoxifen (or nafoxidine) alone does not significantly affect pS2 mRNA levels nor transcription of the pS2 gene but completely antagonizes the ability of estradiol to increase pS2 RNA levels. The estrogen-mediated increase in pS2 mRNA levels resembles that of two estrogen-regulated proteins (52 and 160 kDa) that are released from MCF7 cells into the culture medium. This is distinct from the estrogen-mediated increase in progesterone receptor which is also obtained by tamoxifen treatment. In the two tamoxifen-resistant sublines (R27 and RTx6), tamoxifen does not increase pS2 mRNA levels or 160-kDa protein production but increases the production of the 52-kDa protein. These results show that in these tamoxifen-resistant cells, tamoxifen has become fully estrogenic for one, but not all estrogen-regulated responses.
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PMID:Effects of antiestrogens on the estrogen-regulated pS2 RNA and the 52- and 160-kilodalton proteins in MCF7 cells and two tamoxifen-resistant sublines. 646 52

Of the steroid hormone receptor family members, the estrogen receptor (ER) is notable in containing a sizable (42-amino acid) C-terminal region, denoted domain F. This F region differs from its adjacent hormone-binding domain, domain E, in that it is not well conserved among different vertebrate ER species, and its role in the biological activity of the ER is not well defined. We report an important role for the F domain of the ER in modulating the magnitude of gene transcription by estrogen and antiestrogen, and in determining the effectiveness of antiestrogens in suppressing estrogen-stimulated gene transcription. Using transient transfections, we have examined, in several cell types, the transcriptional activity of the full-length wild type human ER and ER lacking the carboxy-terminal F domain (delta F ER, containing amino acids 1-554) or ER altered in the F domain by point mutations. In some cells, namely Chinese hamster ovary (CHO) cells and MDA-MB-231 human breast cancer cells expressing wild type ER or delta F ER, estradiol (E2) stimulates equally transcription of several estrogen-responsive promoter-reporter gene constructs [estrogen ca-18119 element, (ERE)2-TATA-CAT, (ERE)2-pS2-CAT, (ERE)2-progesterone receptor(distal)-CAT]; however, the antiestrogens trans-hydroxytamoxifen and ICI 164,384, which stimulate transcription of some of these reporter constructs with the wild type ER, were unable to stimulate transcription with delta F ER. In addition, these antiestrogens were more effective antagonists of E2-stimulated transcription by delta F ER than by wild type ER. By contrast, in HeLa human cervical cancer cells and 3T3 mouse fibroblast cells, the delta F ER exposed to E2 is much less effective than wild type ER in stimulating transcription, and antiestrogens were less potent in suppressing E2-stimulated transcription by the delta F ER. These differences in response of the delta F and wild type ER to estrogen or antiestrogen do not appear to be due to a change in receptor expression level, binding affinity for ligands, or binding to estrogen response element DNA. Our data support the supposition that the conformation of the receptor-ligand complex is different with estrogen vs. antiestrogen and with wild type vs. delta F ER, such that its potential for interaction with protein cofactors or transcription factors is different and is markedly influenced by cell context. Thus, the F domain of the ER has a specific modulatory function that affects the agonist/antagonist effectiveness of antiestrogens and the transcriptional activity of the liganded ER in cells.
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PMID:The carboxy-terminal F domain of the human estrogen receptor: role in the transcriptional activity of the receptor and the effectiveness of antiestrogens as estrogen antagonists. 747 65

The deleterious, disruptive effects of estrogen mimics on the endocrine system were discovered after the compounds were released into the environment. Their chemical structure does not obviously resemble that of steroid hormones; hence, their estrogenic effects were totally unexpected. In addition to occupational exposures, environmental estrogens may have played a role in decreasing the quantity and quality of human semen during the last 50 years and in increasing the incidences of testicular cancer and cryptorchidism in men and breast cancer in women and men in industrialized countries. Testing the environmental estrogen hypothesis will require developing appropriate biomarkers of exposure and measuring these biomarkers at developmental points where exposure is critical. We report the ongoing development of a method to extract and separate xenoestrogens from ovarian estrogens with human serum as a source, followed by determination of xenoestrogen concentration by a bioassay. We also critically assess bioassays currently available to measure the cumulative effect of xenoestrogens, e.g., (a) the E-SCREEN assay, which measures the proliferative effect of estrogens on their target cells, and (b) the induction by estrogens of specific gene products, such as progesterone receptor and pS2.
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PMID:Development of a marker of estrogenic exposure in human serum. 749 50

MCF7 human breast cancer cells have been studied extensively as a model for hormonal effects on breast cancer cell growth and specific protein synthesis. Because the proliferative effect of natural estrogen is considered the hallmark of estrogen action, it was proposed that this property be used to determine whether a substance is an estrogen. The E-screen assay, developed for this purpose, is based on the ability of MCF7 cells to proliferate in the presence of estrogens. The aim of our study was to characterize the response of four MCF7 cell stocks (BUS, ATCC, BB, and BB104) and determine which of them performed best in the E-screen test. The four stocks assayed were distinguishable by their biological behavior. In the absence of estrogen, MCF7 BUS cells stopped proliferating and accumulated in the G0/G1 phase of the cell cycle; estrogen receptors increased, progesterone receptors decreased, and small amounts of pS2 protein were secreted. Of all the MCF7 stocks tested, MCF7 BUS cells showed the highest proliferative response to estradiol-17 beta: cell yields increased up to sixfold over those of nontreated cells in a 144-hr period. The differences between estrogen-supplemented and nonsupplemented MCF7 BUS cells were due mostly to G0/G1 proliferative arrest mediated by charcoal dextran-stripped serum. MCF7 BUS cell stocks and others showing a similar proliferative pattern should be chosen for use in the E-screen test, or whenever a proliferative effect of estrogen is to be demonstrated.
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PMID:The E-screen assay: a comparison of different MCF7 cell stocks. 749 97

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

We find that stimulation of the protein kinase A (PKA) signaling pathway in MCF-7 human breast cancer cells changes the agonist/antagonist activity of tamoxifen and related antiestrogens; it activates or enhances their estrogen agonist activity and reduces their ability to antagonize the effects of estradiol (E2). In MCF-7 human breast cancer cells which contain high levels of endogenous estrogen receptor (ER), the antiestrogen trans-hydroxy-tamoxifen (TOT) fails to stimulate transcription of the estrogen-responsive promoter-reporter constructs estrogen response element (ERE)-TATA-chloramphenicol acetyl transferase (CAT), (ERE)2-TATA-CAT, and pS2-CAT. However, when cells are treated with isobutyl methylxanthine plus cholera toxin (which increases intracellular cAMP approximately 10-fold), or with 8-bromo-cAMP, or are transfected with expression vectors for the PKA catalytic subunits, the transcriptional activity of the antiestrogen-ER complex is now increased, to levels 20-75% that of E2, and TOT also becomes much less effective in antagonizing the stimulation of transcription by E2. Although this alteration in the agonist and antagonist activity of TOT is observed with three promoter-reporter constructs, containing a simple TATA promoter or a more complex, pS2 promoter, elevation of cAMP did not enhance the transcription by either TOT or E2 of the reporter plasmid ERE-thymidine kinase-CAT. Thus, this phenomenon is promoter specific. The maximal stimulatory effects of isobutylmethylxanthine plus cholera toxin and PKA catalytic subunits on TOT and E2 transcriptional enhancement were not additive, consistent with the hypothesis that they are both acting via stimulation of the same signal transduction pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alteration in the agonist/antagonist balance of antiestrogens by activation of protein kinase A signaling pathways in breast cancer cells: antiestrogen selectivity and promoter dependence. 751 3

A polymerase chain reaction (PCR) assay was developed to test for tumor cell specific expression of the BCEI gene. This new marker gene, reported at first for human breast cancer, was found specifically active in various gastrointestinal carcinomas by previously applying immunohistochemistry and RNA (Northern blot) analysis. Presently, by using reverse transcription-PCR analysis, a series of primary tumor tissues and established tumor cell lines were tested for BCEI transcription. This approach was compared to immunostaining achieved by an antibody directed against the BCEI gene's product. The result demonstrate the superior sensitivity of PCR by indicating the gene's expression in cases where immunohistochemical testing remained negative.
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PMID:PCR expression analysis of the estrogen-inducible gene BCEI in gastrointestinal and other human tumors. 753 Nov 28

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


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