Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An antiserum to peptide containing 15 amino acids corresponding to the region-D of human estrogen receptors (hERD) was obtained in mice by immunization with the peptide conjngated to KLH. Using this antiserum, the ER status of paraffin-embeded sections of 95 human breast carcinomas (in which, sections of 31 were both frozen and paraffin-embeded ones) were studied. The corresponding rate for determination of ER status between immunohistochemical staining (IHC) and dextran coated charcoal (DCC) assay was 89.5%. The concordance rate for semiquantitative gradings was 69.3%. In addition, in situ hybridization (ISH) of 15 frozen sections of the samples using digoxigenin labeled dUTP to identify the expression of ER mRNA was also done. The result of ISH was fully consistent with that of IHC (100%). The results show that the mouse antiserum to hERD obtained in this study is specific and sensitive for IHC assay of ER and IHC is a valuable adjunct and/or alternative to the biochemical method for determination of the ER status of breast cancer.
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PMID:[Production and application of mouse antiserum to human estrogen receptors]. 869 73

Steroidal antiestrogens appear to have at least two major modes of action in breast cancer cells, direct antagonism of estrogen binding to its receptor and depletion of estrogen receptors (ER) due to inhibition of dimerization of the receptor and a resultant destabilization of the receptor protein. In a search for other classes of compounds which would act as dimerization inhibitors, a novel substituted indole (8-{2-[1-(4-chlorobenzoyl)-5-hydroxy-2-methyl-1H-indol-3-yl]-acetylamino} octanoic acid butyl-methyl amide, MDL 101,906) was synthesized. Binding of the ER to its consensus response element (ERE) was apparently decreased in nuclear extracts from MCF-7 human breast cancer cell treated with MDL 101,906. This decreased binding was found to be due to depletion of ER based on direct measurement of ER using an enzyme-linked immunoassay. Other transcription factors were apparently unaffected by MDL 101,906 treatment. Whereas depletion of ER with a steroidal antiestrogen was almost complete after 3 h of treatment of MCF-7 cells, the effect of MDL 101,906 took significantly longer to occur, suggesting a fundamental difference in the mechanisms of action of the two drugs. This was also evident in the lack of binding of MDL 101,906 to the hormone binding domain of ER. MDL 101,906 treatment also caused depletion of ER mRNA in MCF-7 cells. Depletion of ER mRNA was noted by 3 h of drug treatment and was apparently almost complete after 24 h of treatment. Depletion of ER from MCF-7 cells led to a dose-dependent decrease in the expression of luciferase by an ERE-driven luciferase reporter gene assay system. The mechanism of MDL 101,906 appears to be unique and additional studies with this chemical class seem to be warranted to assess the potential for therapeutic utility.
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PMID:Depletion of estrogen receptor in human breast tumor cells by a novel substituted indole that does not bind to the hormone binding domain. 880 83

In human breast cancer cell lines, an inverse relationship exists between the basal levels of oestrogen receptor (ER) and epidermal growth factor receptor (EGF-R) gene expression. In addition, the tumour-promoting phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) inhibits ER and stimulates EGF-R expression in MCF-7 breast cancer cells. This study aimed to define further the potential mechanisms involved in the modulation of ER and EGF-R gene expression by TPA. ER mRNA levels were reduced after 3 h and declined to 30% of control between 12 and 72 h after exposure to 10 nM TPA. This decrease in mRNA levels was preceded by an apparent fall in ER transcription rate. There was no effect on the stability of ER mRNA following pretreatment for 3-24 h with TPA, supporting the conclusion that the fall in ER mRNA levels was predominantly due to a decrease in ER transcription rate. Levels of EGF-R mRNA increased 10-fold by 12 h due predominantly to an increased transcription rate. The TPA-induced decrease in ER mRNA was unaffected by the simultaneous administration of the protein synthesis inhibitor cycloheximide, whereas the increase in EGF-R mRNA was inhibited by co-incubation with cycloheximide. These data indicate a requirement for continuing protein synthesis for the TPA effect on EGF-R but not on ER mRNA levels. Because the modulation of ER and EGF-R gene expression by TPA is likely to involve the protein kinase C (PKC) signal transduction pathway, the effects of other known activators of PKC were investigated. The non-phorboid tumour promoter mezerein modulated ER (an 80% decrease) and EGF-R (a 20-fold increase) mRNA levels in a similar manner to TPA. In contrast, neither 1,2-dioctanoyl-sn-glycerol (DiC8) nor 1-oleoyl-2-acetyl-sn-glycerol (OAG), both permeant analogues of the endogenous physiological activators of PKC, affected ER and EGF-R mRNA levels. These latter results were not due to a lack of efficacy because a single administration of DiC8 was as effective as TPA in inducing c-fos mRNA at 30 min. However DiC8 was less active in the later induction of c-myc mRNA. These data demonstrate reciprocal regulation of ER and EGF-R gene expression by TPA, involving effects on transcriptional events, which appear to be mediated by sustained activation of PKC.
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PMID:Inverse regulation of oestrogen receptor and epidermal growth factor receptor gene expression in MCF-7 breast cancer cells treated with phorbol ester. 883 62

We have isolated a variant of the MCF-7 human breast tumor that is characterized by a hormone-independent, yet hormone-responsive, phenotype. This tumor, designated MCF-WES, was derived from MCF-7 tumor cells implanted in the mammary fat pad of a nude mouse in the absence of estradiol supplementation. MCF-WES tumors remain responsive to estradiol; however, unlike the parental MCF-7 tumors, they are stimulated to grow by tamoxifen. Additionally, MCF-WES cells are resistant to the pure steroidal antiestrogen, ICI 182,780. To our knowledge, a tumor with this combination of properties has not yet been described. Nuclear estrogen receptor (ER) levels in MCF-WES cells were 10% of those for MCF-7 under steroid-depleted conditions. MCF-WES tumor ER levels were 32% of those in MCF-7 tumors. Similarly, in vivo expression of ER mRNA for MCF-WES was 20% of levels determined for MCF-7. Further characterization of MCF-WES cells showed that they have increased levels of AP-1 DNA-binding activity. The marked increase in AP-1 binding activity may act to bypass the hormone dependence that is a characteristic of MCF-7 cells. It is also probable that the increase in AP-1 binding activity is responsible for the finding that MCF-WES cells secrete greater quantities of metalloproteinase activity in comparison to parental MCF-7 cells, suggesting progression to a more invasive, malignant phenotype. More complete characterization of this new cell line will help elucidate hormone-independent breast cancer and possibly identify targets for therapy.
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PMID:Progression of MCF-7 breast cancer cells to antiestrogen-resistant phenotype is accompanied by elevated levels of AP-1 DNA-binding activity. 883 65

For various human tumor cell lines (neuroblastoma, cervix carcinoma) the presence of constitutive nitric oxide synthase (cNOS) has been documented. Here, for the first time, we report about cNOS expression in 10 of 16 human breast cancer cell lines. cNOS expression correlates strongly with expression of estrogen receptor (ER). Competitive reverse transcription-polymerase chain reaction (cRT-PCR) was used to detect cNOS and ER mRNA expression. Our findings suggest that estradiol could stimulate constitutive NO release in breast tissue, where it acts as a free radical.
Breast Cancer Res Treat 1996
PMID:Simultaneous expression of nitric oxide synthase and estrogen receptor in human breast cancer cell lines. 887 87

The development of antioestrogen resistance is a major clinical obstacle encountered in the treatment of breast cancer. By long-term growth in oestrogen-free medium, we have derived an oestrogen-independent, anti-oestrogen resistant cell line from the oestrogen receptor (ER)-positive, oestrogen-dependent T47D human breast cancer cell line. This cell line grows maximally in oestrogen-free medium and is resistant to all tested antioestrogens. This cell line does not express any measurable amounts of ER mRNA or protein and, in short-term studies, these cells show no response to either oestrogens or antioestrogens. However, return of these cells to oestrogen-containing medium for more than 8 weeks resulted in the re-expression of ER mRNA and protein. Subsequent limiting dilution subcloning of the T47D:C4 line revealed two phenotypically distinct clones, one which did not express measurable ER after long-term growth in oestrogen-containing medium and one which expressed ER mRNA and protein after a number of weeks in oestrogen-containing medium. In the absence of oestrogen, both types of cells are ER-negative as determined by Northern and Western blotting and lack of any oestrogen-dependent responses. The clone which re-expresses the ER (T47D:C4:5W) now responds to E2 with a 50% increase in growth and a 30-fold induction of an ER-responsive luciferase reporter construct. Long-term growth of the stably ER-negative clone (T47D:C4:2W) causes no measurable oestrogen-mediated responses, as assessed by ER expression, growth stimulation or luciferase induction. Interestingly, ER mRNA can be detected in both cell types by using reverse transcriptase-polymerase chain reaction (RT-PCR). This suggests that the ER mRNA present in the T47D:C4:2W clone is either inefficiently translated or is present at such a low level as to be functionally irrelevant. These novel clonal cell lines will prove to be invaluable in the study of the regulation of ER expression and regulatory pathways leading to oestrogen-independent growth.
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PMID:Irreversible loss of the oestrogen receptor in T47D breast cancer cells following prolonged oestrogen deprivation. 888 9

Effects of the pure antiestrogen ICI182780 and tamoxifen on ER-protein, ER-mRNA, and estrogen-regulated mRNA expression were analysed using matched pretreatment core-cut biopsies and post-treatment mastectomy samples from 43 ER positive human breast cancers. Sixteen controls received either no preoperative treatment (n = 9) (7 days) or placebo (n = 7) (median 21 days) prior to primary surgery. Nineteen patients received ICI182780 6 mg/day (n = 10) or 18 mg/day (n = 9) for 7 days. Eight patients were given preoperative tamoxifen (4 x 40 mg-day 1, 20 mg/day thereafter, median 21 days). ER-protein expression was assessed on pre and post treatment samples by immunocytochemistry. ER, pS2, pLIV1, and actin-mRNA expression was determined by northern analysis on post-treatment samples only. ER-mRNA levels were similar to controls following ICI182780 or tamoxifen treatment. However ER-protein levels were significantly suppressed by ICI182780, particularly at the higher dosage (p = 0.0013). Tamoxifen had no significant effect on ER-protein levels. The ER-mRNA and ER-protein contents of control tumors were linearly related (Spearman r = 0.719, p = 0.006). A similar relationship between pretreatment protein and post ICI182780 treatment mRNA levels was observed (r = 0.652, p = 0.005). However, comparison of post ICI182780 treatment protein and mRNA results shows a loss of linearity through a reduction in protein without concurrent loss of mRNA (r = 0.28, p = 0.257). pS2 mRNA hybridization was lower in ICI182780 treated samples than controls (Mann-Whitney p = 0.035) but was unaffected by tamoxifen. pLIV1 mRNA hybridization was uninfluenced by either treatment. Short term exposure of breast tumors to ICI182780 appears to produce a greater inhibition of estrogen-induced transcriptional events than tamoxifen. These effects appear to occur without a concurrent reduction in ER mRNA levels.
Breast Cancer Res Treat 1996
PMID:Effects of short-term antiestrogen treatment of primary breast cancer on estrogen receptor mRNA and protein expression and on estrogen-regulated genes. 893 74

Breast cancers lacking estrogen receptor (ER) expression have an adverse prognosis and fail to respond to endocrine therapy. We have identified a transcriptional enhancer in the human ER gene which is differentially active in ER-positive (ER+) and ER-negative (ER-) human breast cancer cell lines. Enhancer function was mapped to a 35-bp element located from -3778 to -3744 upstream of the major human ER mRNA start site, which we have termed ER-EH0 (for estrogen receptor enhancer). Gel retardation assays with ER+ and ER- cell lines identified multiple DNA-protein complexes which specifically form on this enhancer. One of these complexes could be supershifted by anti-Jun or anti-Fos antibodies, identifying it as an AP-1-containing complex. Methylation interference assays suggest binding of factors to both the AP-1 site and adjacent base pairs. Enhancer activity requires both the AP-1 site and these adjacent sequences. Mutations introduced into ER-EH0 and the recently described proximal promoter element ERF-1 in the context of the full-length promoter confirm ER-EH0 as the dominant cis-acting element involved in differential ER expression.
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PMID:A transcriptional enhancer required for the differential expression of the human estrogen receptor in breast cancers. 903 54

It was reported previously that low-density lipoproteins (LDL) differentially stimulate cell growth of hormone-responsive (ER+) and hormone-unresponsive (ER-) mammary tumor cell lines. Here we examined the mRNA levels of the LDL-receptor (LDL-R) gene with RNAse protection analysis in ER- (MDA-MB-231 and HBL-100) and ER+ (MCF-7 and ZR75-1) cells, and compared them with the estrogen receptor (ER) status. Measurable amounts of ER mRNA were only found in ER+ cells as expected. LDL-R mRNA abundance was 3-5 fold higher in ER- cells as compared to ER+ cells. Incubation with phorbol-12-myristate-13-acetate led to a significant increase (p < 0.005) of LDL-R mRNA in ER+ cells, whereas in ER- cells LDL-R mRNA levels remained merely unchanged. Incubation of cells with dioctanoylglycerol, a synthetic homolog of diacylglycerol, increased LDL-R mRNA in ER+ but not in ER-. Inhibition of protein kinase C (PKC) by H7 resulted in a highly significant reduction of LDL-R mRNA both in ER+ and ER- cells. PKC seems to be an important regulator of LDL-R mRNA abundance in mammary tumor cells. It is hypothesized that in human-breast cancer the process of conversion from hormone-responsive to hormone-unresponsive status is accompanied by a change in PKC activity and PKC might exert cell specific differences on the regulation of LDL-R mRNA levels, which in turn influences the delivery of exogenous cholesterol to cancer cells.
Breast Cancer Res Treat 1997 Feb
PMID:Low-density lipoprotein receptor mRNA in human breast cancer cells: influence by PKC modulators. 906 3

The human estrogen receptor (ER) gene has recently been shown to transcribe two types of mRNA originating from two distinct promoters in mammary tumor cell lines, which encode the same protein. However, use of the two promoters has not been addressed in human breast cancer, which reveals a heterogeneity in terms of ER expression status and clinical characteristics. In this report, we investigated which promoter is responsible for the expression of ER in human mammary tumors by a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis for discriminatory detection of the two transcripts in mammary tissues obtained from patients with breast cancer. First, the use of distinct promoters was confirmed in several mammary tumor cell lines by the present RT-PCR method. Secondly, expression levels of total ER mRNA and two types of mRNAs from the different promoters were analysed in tumor, surrounding tissue and normal tissue obtained from 12 patients with breast cancer, which showed various levels of ER protein. In tumors, levels of total ER mRNA and the mRNA transcribed from a distal promoter showed remarkable correlation to the ER protein levels with correlation coefficients 0.946 (P < 0.001) and 0.746 (P < 0.005), respectively. In contrast, mRNA from a proximal promoter showed no correlation to the ER protein levels. Our results indicate that the enhancement of the ER mRNA expression from the distal promoter plays an essential role in the mechanisms of overexpressing ER protein in human mammary tumors, implying that a tumor-specific regulation of ER expression involved use of the distal promoter.
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PMID:Two promoters in expression of estrogen receptor messenger RNA in human breast cancer. 906 42


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