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Query: UNIPROT:P04155 (pS2)
 1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of the erbB-2 oncogene in breast cancer patients correlates with poor prognosis and failure of hormonal therapy. In this study, the effects of a putative erbB/HER ligand, gp30, on estrogen receptor (ER) concentration and activity was investigated in the estrogen receptor positive human breast cancer cells, BT474 and MCF-7, which express either high or low levels of erbB-2 and erbB-4, respectively. Treatment of cells with gp30 resulted in a decrease in the steady-state level of estrogen receptor protein by approximately 70-80%. The effect of gp30 on the concentration of ER was independent of serum in the media and was not inhibited by an epidermal growth factor receptor blocking antibody. In addition to the effect on ER protein, gp30 decreased the steady-state level of ER messenger RNA. Transcription run on experiments demonstrated that the decrease in ER expression was mediated by a decrease in ER gene transcription. The effect of gp30 on estrogen receptor activity was also investigated in this study. Treatment of cells with gp30 blocked estradiol induction of progesterone receptor. Inhibition was observed at the level of progesterone receptor protein, messenger RNA, and gene transcription. gp30 also blocked estradiol induction of pS2 gene transcription. In addition to its effects on progesterone receptor and pS2, gp30 blocked activation of an estrogen response element in a transient transfection assay and inhibited ER binding to its response element in a DNA mobility shift assay, suggesting a direct effect on the estrogen receptor. The effects of gp30 on estrogen receptor concentration and activity were independent of the level of erbB-2 and erbB-4 in the cell. These data show that gp30 regulates the concentration of ER and modulates ER activity.
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PMID:Regulation of estrogen receptor concentration and activity by an erbB/HER ligand in breast carcinoma cell lines. 882 92

Two new immunoenzymatic assays for c-erbB-2 oncoprotein and epidermal growth factor receptor (EGF-R) (Oncogene Science) in human breast cancer were validated. Correlations between these assays and some clinical and biological parameters were also studied. The repeatability and reproducibility of standard curves for the two methods gave a coefficient of variation (CV) of less than 4% and about 10% respectively. The accuracy of c-erbB-2 oncoprotein and EGF-R assays was examined by using dilution and recovery tests throughout the standard curves. The linear relations between theoretical and measured values, for these tests, had slopes close to 1 and an intercept near 0. The median value for EGF-R, measured on solubilized membranes of 290 primary tumors, was 0.12 fmol/micrograms protein, the mean value was 0.37 (range 0 to 35.7). For c-erbB-2 oncoprotein, the median value, measured using the same population, was 2.75 human neu unit/micrograms protein, the mean value was 7.85 (range 1 to 125). There was an inverse relationship between EGF-R values and those for the estrogen receptor (ER), progesterone receptor and pS2 protein as well as menopausal status. C-erbB-2 oncoprotein concentrations were positively correlated with ER, pS2 protein and cathepsin D. Furthermore, a significant positive correlation was observed between EGF-R levels and c-erbB-2 oncoprotein levels. In conclusion, immunoenzymatic assays of EGF-R and c-erbB-2 oncoprotein are easy to use, sensitive and reliable. The accurate standardisation of immunoenzymatic assays could contribute to the clinical use of EGF-R and c-erbB-2 oncoprotein as prognostic factors in breast cancer.
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PMID:[Immunoenzymatic assays of c-erbB-2 oncoprotein and epidermal growth factor receptor in breast cancer: correlation with clinical and biological parameters]. 888 58

We tested some resin-based composites used in dentistry for their estrogenic activity. A sealant based on bisphenol-A diglycidylether methacrylate (bis-GMA) increased cell yields, progesterone receptor expression, and pS2 secretion in human estrogen-target, serum-sensitive MCF7 breast cancer cells. Estrogenicity was due to bisphenol-A and bisphenol-A dimethacrylate, monomers found in the base paste of the dental sealant and identified by mass spectrometry. Samples of saliva from 18 subjects treated with 50 mg of a bis-GMA-based sealant applied on their molars were collected 1 hr before and after treatment. Bisphenol-A (range 90-931 micrograms) was identified only in saliva collected during a 1-hr period after treatment. The use of bis-GMA-based resins in dentistry, and particularly the use of sealants in children, appears to contribute to human exposure to xenoestrogens.
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PMID:Estrogenicity of resin-based composites and sealants used in dentistry. 1113 9

To understand better the antiestrogen-resistant phenotype that frequently develops in breast cancer patients receiving tamoxifen, we cultured MCF-7 breast cancer cells long-term (>1 yr) in the presence of the antiestrogen trans-hydroxytamoxifen (TOT) to generate a subline refractory to the growth-suppressive effects of TOT. This subline (designated MCF/TOT) showed growth stimulation, rather than inhibition, with TOT and diminished growth stimulation with estradiol (E2), yet remained as sensitive as the parental cells to growth suppression by another antiestrogen, ICI 164,384. Estrogen receptor (ER) levels were maintained at 40% of that in parent MCF-7 cells, but MCF/TOT cells failed to show an increase in progesterone receptor content in response to E2 or TOT treatment. In contrast, the MCF/TOT subline behaved like parental cells in terms of E2 and TOT regulation of ER and pS2 expression and transactivation of a transiently transfected estrogen-responsive gene construct. DNA sequencing of the hormone binding domain of the ER from both MCF-7 and MCF/TOT cells confirmed the presence of wild-type ER and exon 5 and exon 7 deletion splice variants, but showed no point mutations. Compared to the parental cells, the MCF/TOT subline showed reduced sensitivity to the growth-suppressive effects of retinoic acid and complete resistance to exogenous TGF-beta1. The altered growth responsiveness of MCF/TOT cells to TOT and TGF-beta1 was partly to fully reversible following TOT withdrawal for 16 weeks. Our findings underscore the fact that antiestrogen resistance is response-specific; that loss of growth suppression by TOT appears to be due to the acquisition of weak growth stimulation; and that resistance to TOT does not mean global resistance to other more pure antiestrogens such as ICI 164,384, implying that these antiestrogens must act by somewhat different mechanisms. The association of reduced retinoic acid responsiveness and insensitivity to exogenous TGF-beta with antiestrogen growth resistance in these cells supports the increasing evidence for interrelationships among cell regulatory pathways utilized by these three growth-suppressive agents in breast cancer cells. In addition, our findings indicate that one mechanism of antiestrogen resistance, as seen in MCF/TOT cells, may involve alterations in growth factor and other hormonal pathways that affect the ER response pathway.
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PMID:Response-specific antiestrogen resistance in a newly characterized MCF-7 human breast cancer cell line resulting from long-term exposure to trans-hydroxytamoxifen. 901 Mar 27

The estrogen receptor (ER) is a ligand-regulated transcription factor that acts at the promoters of estrogen-regulated genes to modulate their expression. In the present study, we examined three estrogen-regulated promoters, namely the rat progesterone receptor gene distal (PRD) and proximal (PRP) promoters and the human pS2 gene promoter, and observed marked differences in their sensitivity to stimulation by estrogen and repression of estrogen-stimulated transcription by antiestrogen (AE)-occupied ER. ER-containing MCF-7 human breast cancer cells were transfected with reporter gene constructs containing estrogen response elements upstream of the three gene promoters. In this system, PRP and PRD showed similar dose-response curves for stimulation by estradiol whereas pS2 was activated by even lower concentrations of estradiol. By contrast, PRD was much less sensitive to repression of estrogen-stimulated activity by all AEs studied, relative to the PRP and the pS2 promoters. Using deletion and mutational analysis, we have identified a transferable cis element at -131 to -94 bp in PRD that is involved in modulating the sensitivity of this promoter to both estrogens and AEs. The element reduced the magnitude of estrogen-stimulated activity, enhanced the ability of AEs to repress estrogen-stimulated activity, and elicited similiar effects when transferred to the promoter of another estrogen-responsive gene. Thus, removal of this region from PRD further accentuated the insensitivity of this promoter to AE while enhancing its sensitivity (both EC50 and fold induction) to estrogen. Gel mobility shift assays showed that proteins from nuclear extracts of MCF-7 cells interact with this element and that the binding of these proteins is inversely correlated with the transcriptional effectiveness of the ER. The findings demonstrate that a specific cis element from the promoter of an estrogen-responsive gene can alter the transcriptional activity of hormone and antihormone-occupied receptor bound at its response element near the promoter. Such ligand response modulatory elements, and changes in the levels and activity of factors that bind to such elements, may underlie the different sensitivities of steroid hormone-regulated genes to both hormones and antihormones.
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PMID:Identification of a novel transferable cis element in the promoter of an estrogen-responsive gene that modulates sensitivity to hormone and antihormone. 905 79

The estrogen regulated pS2 protein and the Plasminogen Activator Inhibitor type 1 (PAI-1) have been reported as important tumor parameters both in breast and in ovarian cancer. We analysed the cytosolic concentrations of pS2 in 111 ovarian carcinoma and the cytosolic concentrations of PAI-1 in 104 ovarian cancers by RIA and ELISA. Using a cut-off level of 2 ng/mg protein we found 27% pS2+ tumors. We observed 42% PAI-1+ tumors using a out-off level of 1 ng/mg. We found a statistically significant decline in the pS2 status corresponding with an increase in the PAI-1 status from well to poor differentiation grade. The highest levels of pS2 and the lowest levels of PAI-1 were measured in borderline carcinoma. Significantly higher concentrations of pS2 were measured in mucinous over serous carcinoma. We found no significant correlation between PAI-1 and histologic subtypes, or between pS2 or PAI-1 and estrogen receptor status, progesterone receptor status, age and tumor stage. To conclude, we found pS2 and PAI-1 concentrations to be correlated with the grade of differentiation. A correlation between protein status and histologic subtypes could be observed for pS2 but not for PAI-1.
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PMID:pS2 and PAI-1 in ovarian cancer: correlation to pathohistological parameters. 906 1

The role of transforming growth factor-beta1 (TGFbeta1) in the regulation of estrogen receptor (ER) expression in MCF-7 cells was investigated. After treatment of the cells with 100 pM TGFbeta1, ER protein declined by about 30% at 6 h from a concentration of 413.5 fmol/mg protein in control cells to 289.5 fmol/mg protein in treated cells. The concentration of receptor remained suppressed for 24 h. Scatchard analysis demonstrated that the decrease in ER protein corresponded to a decrease in estradiol-binding sites, with no effect on the binding affinity of the ER. The dissociation constant of the estradiol-ER complex was 0.117 nM in TGFbeta1-treated cells compared to 0.155 nM in control cells. Treatment with TGFbeta1 did not influence the half-life of the ER. In TGFbeta1-treated cells, as well as in control cells, the half-life of the receptor was approximately 4 h. In contrast to the effect on ER concentration, TGFbeta1 treatment resulted in a greater decrease in the steady state level of ER messenger RNA (approximately 75%) at 6 h. By 24 h, a small recovery in the amount of messenger RNA was observed. Transcription run-on experiments demonstrated a decrease of approximately 70% in the level of ER gene transcription at 3 h. Transient transfections using an ER promoter-chloramphenicol acetyltransferase construct demonstrated that after TGFbeta1 treatment, chloramphenicol acetyltransferase activity decreased by 50%, suggesting that TGFbeta1 inhibition of the ER gene transcription is mediated through the ER promoter. Although treatment with TGFbeta1 decreased the ER concentration, the growth factor had no effect on the activity of ER, as measured by its effects on estradiol induction of progesterone receptor and pS2, suggesting that TGFbeta1 does not inhibit proliferation of MCF-7 cells by blocking ER activity.
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PMID:The role of transforming growth factor-beta in the regulation of estrogen receptor expression in the MCF-7 breast cancer cell line. 907 8

Using immunohistochemistry, we examined pS2 expression in 64 samples of endometrial carcinoma, 11 samples of endometrial hyperplasia and 15 samples of normal endometrium, and compared them with clinicopathological data, estrogen receptor (ER) expression and progesterone receptor (PR) expression. Of the 64 samples of endometrial carcinoma, 45 (70%) expressed the pS2 protein. The average age of the patients with pS2-positive carcinomas (54.8 +/- 8.6 years) was significantly lower than that of the patients with pS2-negative carcinomas, and all premenopausal patients were positive for the pS2 protein. Among histological types, pS2 expression was observed in 33 (92%) of the 36 G1 carcinomas, but in none of the 5 nonendometrioid carcinomas. Of the 48 ER-positive carcinomas, 43 (90%) were pS2-positive and 5 were pS2-negative. Of the 40 PR-positive carcinomas, 37 (93%) were positive for pS2. There were significant associations between pS2 expression and ER/PR expression (p < 0.001). Staining of the pS2 protein was also observed in the samples of normal endometrium. We found a progressive increase in immunoreactivity of pS2 protein from normal endometrium to endometrial hyperplasia and still more in well-differentiated carcinoma. All 11 cases of endometrial hyperplasia were strongly positive for pS2. Furthermore, patients with pS2-positive carcinomas had a better survival rate than those with pS2-negative carcinomas (p < 0.05). Our data suggest that pS2 expression is likely correlated with estrogen-related endometrial carcinoma and is possibly involved in early disease progression.
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PMID:Expression of pS2 protein in endometrial carcinomas: correlation with clinicopathologic features and sex steroid receptor status. 922 98

To elucidate the mechanisms responsible for the development of anti-estrogen resistance, we have cloned and established 3 stable ICI-182,780-resistant sub-lines, MCF-7/182R-1, MCF-7/182R-6 and MCF-7/182R-7 from the estrogen-receptor(ER)-positive and estrogen-responsive human breast-cancer MCF-7 cell line by long-term treatment with 10(-7) M ICI 182,780. The ICI-182,780-resistant MCF-7 sub-lines express ER, but compared with MCF-7 cells the level is significantly lower in all 3 sub-lines. In the MCF-7 cell line we find that ER expression is regulated by estrogen and anti-estrogens at the transcriptional and post-transcriptional level. This is in contrast to the ICI-182,780-resistant sub-lines, in which we find very little hormonal effects on the ER mRNA expression level. The resistant sub-lines also deviate from parent characteristics by the complete lack of expression of progesterone receptor even when grown in the presence of estradiol. All 3 resistant sub-lines have a lower basal expression of cathepsin-D mRNA comparable with the lower ER expression, but, in contrast, they have higher basal expression of the pS2 mRNA than the parent MCF-7 cell line. Although there are different basal expression levels of the pS2 and cathepsin-D genes, the resistant sub-lines behave like the parent MCF-7 cell line with respect to the hormonal regulation of both genes. The estrogen receptors in the resistant sub-lines have also maintained wild-type characteristics with respect to estrogen and anti-estrogen regulation of the estrogen-regulated proteins procathepsin D, alpha1-antitrypsin and a 42-kDa protein. The resistant cells require estrogen for growth in athymic nude mice. Our results clearly demonstrate that the ER in the resistant sub-lines have a normal function for most parameters investigated, supporting our earlier observation that only wild-type ER protein is expressed in these cells. The few observed differences in ER function between the parent MCF-7 cell line and the resistant sub-lines are not likely to be responsible for the ICI-182,780-resistant phenotype.
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PMID:Resistance of human breast-cancer cells to the pure steroidal anti-estrogen ICI 182,780 is not associated with a general loss of estrogen-receptor expression or lack of estrogen responsiveness. 937 50

Estrogen (E) inhibits the growth of both non-tumorigenic, immortal human mammary epithelial cells (HMEC) and breast cancer cells which stably express exogenous estrogen receptors (ER). The anti-estrogenic compounds 4-hydroxy-tamoxifen (HT) and ICI 164384 (ICI) have different effects on the growth of the ER-transfectants. HT is a potent growth inhibitor, while ICI has no effect by itself but is able to block the anti-proliferative effects of E and HT. In order to elucidate the mechanism by which E or HT-bound ER inhibit cell growth, we have evaluated the effects of these compounds on the growth of HMEC stably expressing ER with mutations or deletions in the N-terminal A/B domain, the DNA-binding domain (DBD), and the C-terminal ligand-binding domain. These studies revealed that E and HT require different structural domains of the ER for their anti-proliferative activities. The N-terminal A/B domain is required for HT-, but not E-dependent growth inhibition. The DNA-binding domain of the ER is not essential for HT-mediated anti-proliferative effects, but is important for E-dependent activity. The effect of ER mutations on the ligand-inducible expression of the endogenous progesterone receptor (PR) and pS2 genes was also evaluated. Neither gene was induced in the cells containing the ER mutated in the DBD, even though cell growth was inhibited. These results suggest that E and HT use different pathways to elicit their anti-proliferative effects and that this occurs via modulation of genes that are controlled by mechanisms different from those important for activation of the PR and pS2 genes.
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PMID:Different estrogen receptor structural domains are required for estrogen- and tamoxifen-dependent anti-proliferative activity in human mammary epithelial cells expressing an exogenous estrogen receptor. 944 40


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