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)

When deprived of steroid in the long term, both estrogen-dependent (ZR-75-1) and estrogen-responsive (T-47-D) human breast cancer cells lose estrogen regulation of cell growth in a reproducible time course using both stock lines and recloned cells. The estrogen-stimulated growth rate was unaffected by such treatment, but there was an increase in the basal growth rate without steroid. For ZR-75-1 cells, the effects are clonal but occur at high frequency (1 in 1000 cells) and synchronously between clones, suggesting a phenotypic mechanism. These changes in cell growth occur without any coordinated loss of estrogen sensitivity of molecular markers (pS2 mRNA, progesterone receptor protein) showing that functional estrogen receptors remain present throughout. The constitutive expression of progesterone receptor in one clone of steroid-deprived ZR-75-1 cells does suggest, however, that alterations in expression of individual estrogen-sensitive genes can occur. Loss of estrogen-stimulated growth was not accompanied by loss of growth inhibition by antiestrogen, and the latter effect remained reversible by estradiol. In an attempt to understand the molecular mechanisms underlying the loss of steroid sensitivity in the two cell lines, growth factor gene expression was investigated. Progression to steroid autonomy in T-47-D cells was accompanied by an upregulation of transforming growth factor (TGF) alpha, TGF beta 1, and TGF beta 2 mRNA. However, TGF beta 1 mRNA was downregulated in two ZR-75-1 steroid-deprived clones. These findings are discussed in relation to possible autocrine mechanisms in the loss of steroid sensitivity of breast cancer cells.
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PMID:Cellular and molecular events in loss of estrogen sensitivity in ZR-75-1 and T-47-D human breast cancer cells. 239 57

Stimulation of transcription of reporter genes by the progesterone receptor (PR) was inhibited in transfected HeLa cells by co-expressing the estrogen receptor (ER) in an ER-dose- and estrogen-dependent manner. Both the N-terminal A/B region and the hormone binding domain of ER were involved in this inhibition, which was antagonized by antiestrogens and did not appear to involve direct interaction between ER and either reporter gene or PR. ER expression also inhibited activation by the glucocorticoid receptor (GR), and both PR and GR expression inhibited activation by ER, albeit to a lower extent. Similar transcriptional interference was observed between the endogenous PR and ER present in T47D and MCF-7 breast cancer cells transfected with an ER reporter gene. Moreover, transcription of the resident estrogen-induced pS2 gene was partially inhibited by exposing MCF-7 cells to progestins or glucocorticoids. We propose that these observations reflect competition for a functionally limiting transcription factor(s).
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PMID:Steroid hormone receptors compete for factors that mediate their enhancer function. 272 Jul 78

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

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

Determination of steroid receptors and several oestrogen-regulated proteins in mammary carcinomas is useful in the prediction of their evolution and of the likely success of endocrine therapy. Cathepsin D (Cat D), pS2 peptide and heat shock protein 27 (Hsp 27) were detected immunohistochemically in 63 infiltrating ductal (NOS) breast carcinomas, and our results were qualitatively correlated with several clinicopathological indicators and patients' overall survival. Cat D immunostaining of tumour cells was strongly associated with axillary nodal involvement (Pf = 0.0005) and so, it is directly connected with the metastatic capacity of malignant cells. pS2 immunoreactivity was correlated with oestrogen and progesterone receptor positivity (Pf = 0.0009 and Pf = 0.05 respectively) and, nonsignificantly, with good differentiation of the tumours (Pf = 0.06). Neoplastic cells expressing this protein are therefore characterised by a highly organised state of cellular physiology. Hsp 27 was expressed predominantly in tumours with one to four infiltrated lymph nodes (Pt = 0.05), and Hsp 27-positive patients were inclined to rather short survival, possibly due to chemotherapy resistance. In future, prognostic estimation of each one of the examined markers should be performed in specific large subgroups of patients. The findings of this study contribute to the establishment of criteria by which these subgroups should be formed.
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PMID:Prognostic evaluation of oestrogen-regulated protein immunoreactivity in ductal invasive (NOS) breast cancer. 755 43

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 growth-inhibitory actions of the pineal hormone, melatonin, on human breast tumor cells and the possible association between this inhibition and melatonin's down-regulation of the estrogen receptor (ER) expression were examined in the ER-positive, estrogen-responsive MCF-7 human breast tumor cell line. As previously reported, melatonin dramatically inhibits the growth of these breast tumor cells and down-regulates ER levels in these cells, suggesting that the modulation of ER may be an important mechanism by which melatonin inhibits breast cancer cell growth. In the present studies, Northern blot analysis was used to examine the expression of estrogen-regulated transcripts known to be involved in estrogen's mitogenic actions. Melatonin, at a physiologic concentration (10(-9) M), rapidly, significantly, and, in some cases, transiently elevated the steady-state mRNA levels of growth stimulatory products such as TGF alpha, c-myc, and pS2, which are normally up-regulated in response to estrogen. Conversely, melatonin decreased the expression of other factors normally up-regulated by estrogen, such as progesterone receptor and c-fos. Significant stimulation of the expression of the growth-inhibitory factor TGF beta was seen with melatonin treatment, potentially supporting the concept that melatonin's growth-inhibitory activity is mediated through the breast tumor cells' estrogen-response pathway. The early regulation of many of these products by melatonin suggests that mechanisms more rapid than the down-regulation of ER are important in melatonin's modulation of their expression. However, the long-term modulation of these transcripts (12-48 hr) may be heavily influenced by melatonin's down-regulation of ER expression. These results clearly define the need for additional in depth studies to dissect the cellular events leading to melatonin-induced growth inhibition in breast tumor cells.
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PMID:Melatonin modulation of estrogen-regulated proteins, growth factors, and proto-oncogenes in human breast cancer. 762 97


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