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)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental toxin that activates the aryl hydrocarbon receptor (AhR) and disrupts multiple endocrine signaling pathways. T47D human breast cancer cells express a functional estrogen receptor alpha (ERalpha) and AhR, and treatment of these cells with 17beta-estradiol (E2) or TCDD resulted in a rapid proteasome-dependent decrease in immunoreactive ERalpha and AhR proteins (>60-80%), respectively. E2 did not affect the AhR, whereas TCDD induced proteasome-dependent degradation of both the AhR and ERalpha in T47D and MCF-7 human breast cancer cells, and these responses were specifically blocked by proteasome inhibitors. Thus, TCDD-induced degradation of ERalpha may contribute to the antiestrogenic activity of AhR agonists and this pathway may be involved in AhR-mediated disruption of other endocrine responses.
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PMID:Crosstalk between estrogen receptor alpha and the aryl hydrocarbon receptor in breast cancer cells involves unidirectional activation of proteasomes. 1092 79

Raloxifene belongs to the group of selective estrogen receptor modulators (SERMs). It interacts with both estrogen receptor alpha and beta, but the postreceptor responses differ from those of estrogens. Raloxifene exerts tissue specific responses that differ from estrogens. The drug increases bone mass by 2-3% and inhibits the risk of subsequent vertebral fractures by 30-50%. Raloxifene reduces the risk of breast cancer by 76% after treatment for four years and builds an atrophic endometrium without any bleedings. Furthermore, the risk of endometrial cancer is not increased. The drug exerts positive effects on plasma lipids, but the effects of these changes on subsequent risk of myocardial infarction and cardiovascular death are still unknown. The main side effects are leg cramps, increases in hot flushes and peripheral oedema. Like estrogen, the drug increases the relative risk for venous thrombosis by a factor three.
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PMID:[Raloxifene]. 1096 34

Estrogen rapidly activates the mitogen-activated protein kinases, Erk-1 and Erk-2, via an as yet unknown mechanism. Here, evidence is provided that estrogen-induced Erk-1/-2 activation occurs independently of known estrogen receptors, but requires the expression of the G protein-coupled receptor homolog, GPR30. We show that 17beta-estradiol activates Erk-1/-2 not only in MCF-7 cells, which express both estrogen receptor alpha (ER alpha) and ER beta, but also in SKBR3 breast cancer cells, which fail to express either receptor. Immunoblot analysis using GPR30 peptide antibodies showed that this estrogen response was associated with the presence of GPR30 protein in these cells. MDA-MB-231 breast cancer cells (ER alpha-, ER beta+) are GPR30 deficient and insensitive to Erk-1/-2 activation by 17beta-estradiol. Transfection of MDA-MB-231 cells with a GPR30 complementary DNA resulted in overexpression of GPR30 protein and conversion to an estrogen-responsive phenotype. In addition, GPR30-dependent Erk-1/-2 activation was triggered by ER antagonists, including ICI 182,780, yet not by 17alpha-estradiol or progesterone. Consistent with acting through a G protein-coupled receptor, estradiol signaling to Erk-1/-2 occurred via a Gbetagamma-dependent, pertussis toxin-sensitive pathway that required Src-related tyrosine kinase activity and tyrosine phosphorylation of tyrosine 317 of the Shc adapter protein. Reinforcing this idea, estradiol signaling to Erk-1/-2 was dependent upon trans-activation of the epidermal growth factor (EGF) receptor via release of heparan-bound EGF (HB-EGF). Estradiol signaling to Erk-1/-2 could be blocked by: 1) inhibiting EGF-receptor tyrosine kinase activity, 2) neutralizing HB-EGF with antibodies, or 3) down-modulating HB-EGF from the cell surface with the diphtheria toxin mutant, CRM-197. Our data imply that ER-negative breast tumors that continue to express GPR30 may use estrogen to drive growth factor-dependent cellular responses.
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PMID:Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. 1104 79

The estrogen receptor alpha (ER) is a ligand-dependent transcription factor that plays a critical role in the development and progression of breast cancer, in part, by regulating target genes involved in cellular proliferation. To identify novel components that affect the ER transcriptional response, we performed a genetic screen in yeast and identified RDI1, a Rho guanine nucleotide dissociation inhibitor (Rho GDI), as a positive regulator of ER transactivation. Overexpression of the human homologue of RDI1, Rho GDIalpha, increases ERalpha, ERbeta, androgen receptor, and glucocorticoid receptor transcriptional activation in mammalian cells but not activation by the unrelated transcription factors serum response factor and Sp1. In contrast, expression of constitutively active forms of RhoA, Rac1, and Cdc42 decrease ER transcriptional activity, suggesting that Rho GDI increases ER transactivation by antagonizing Rho function. Inhibition of RhoA by expression of either the Clostridium botulinum C3 transferase or a dominant negative RhoA resulted in enhanced ER transcriptional activation, thus phenocopying the effect of Rho GDI expression on ER transactivation. Together, these findings establish the Rho GTPases as important modulators of ER transcriptional activation. Since Rho GTPases regulate actin polymerization, our findings suggest a link between the major regulators of cellular architecture and steroid receptor transcriptional response.
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PMID:Rho GTPases as modulators of the estrogen receptor transcriptional response. 1106 Feb 89

The synthesis of a series of 35 substituted 3,4-diphenyl quinolines and isoquinolines is described. The majority of these molecules differ from all other triphenylethylene based antiestrogens by a different spatial location of the aminoalkyl side chain. The binding affinity of the most representative molecules (8, 9, 19, 20, 21, 23 and 25), including analogues 8 and 21 without the side chain, for the estrogen receptor alpha (ER) was determined. The ability of these molecules to induce the progesterone receptor was also studied. Antiproliferative activity was evaluated on MCF-7 human breast cancer cells, while intrinsic cytotoxic/cytostatic properties resulting from interaction with other targets than ER were assayed on L1210 murine leukemia cells. Introduction of an aminoalkylamino side chain at carbon 2 confers strong cytotoxic properties to diphenylquinolines 9 and 10 as well as pure antiestrogenic activities. However, cytotoxicity is so high with respect to antiestrogenicity that the latter was clearly observable only in one case (9b). The structure of compound 9b was determined by X-ray crystallography. Molecular modeling of its docking within the hormone-binding domain of the receptor was subsequently undertaken. According to our results, the design of molecules with the side chain bound to the ethylene part of the triphenyl ethylene skeleton might generate compounds of potential pharmacological interest.
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PMID:Diphenyl quinolines and isoquinolines: synthesis and primary biological evaluation. 1109 48

We have previously shown that the distal promoter (promoter B) of the estrogen receptor alpha (ER alpha) gene is responsible for the enhanced expression of the ER alpha gene seen in human breast cancer and that a novel trans-acting factor, estrogen receptor promoter B associated factor 1 (ERBF-1), is required for transcription from promoter B in breast cancer cells. In development of breast cancer, loss of ER alpha gene expression is one of the most important steps in acquiring hormone resistance, though the mechanisms are poorly understood. Recent studies have reported that methylation of the ER alpha gene promoter A and exon 1 was inversely associated with ER alpha gene expression in human breast cancer and cell lines. The methylation status of the promoter B region, which is responsible for overexpression of ER alpha protein in cancer tissue, has not been investigated. In this report, we found that the methylation status of promoter B, as well as that of promoter A, was inversely associated with ER alpha gene expression in human breast cancer and cell lines. Specific methylation of ER alpha gene promoters in vitro directly decreased transcription of the ER alpha gene in a reporter assay. Demethylating treatment induced transcription of ER alpha mRNA from promoter B in ZR-75-1 cells, which showed no transcription from promoter B, despite weak ERBF-1 expression, but not in ER alpha-negative MDA-MB-231 and BT-20 cells, which lack ERBF-1. ZR-75-1 cells showed promoter activity equal to that of MCF-7 cells in a reporter assay. Our results indicate that methylation of promoter B of the ER alpha gene is important for loss of ER alpha gene expression in human breast cancer, and methylation of the promoters can directly modulate ER alpha gene expression. However, loss of critical transcriptional factors such as ERBF-1 may also be involved in some ER alpha-negative cases.
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PMID:Distinct mechanisms of loss of estrogen receptor alpha gene expression in human breast cancer: methylation of the gene and alteration of trans-acting factors. 1113 8

17beta-Estradiol (E2) induces c-fos protooncogene expression in MCF-7 human breast cancer cells, and deletion analysis of the c-fos promoter showed that the serum response element (SRE) at -325 to -296 was E2-responsive. The mechanism of ligand-activated estrogen receptor alpha (ERalpha)-dependent activation of gene expression through the SRE was determined by mutational analysis of the promoter, analysis of mitogen-activated protein kinase (MAPK) pathway activation by E2, and transforming growth factor alpha (TGF-alpha) as a positive control. In addition, ERalpha-negative MDA-MB-231 breast cancer and Chinese hamster ovary cells were used as reference cell lines. The results showed that transcriptional activation of the SRE by E2 was due to ERalpha activation of the MAPK pathway and increased binding of the serum response factor and Elk-1 to the SRE. Subsequent studies with dominant negative Elk-1, wild type, and variant GAL4-Elk-1 fusion proteins confirmed that phosphorylation of Elk-1 at serines 383 and 389 in the C-terminal region of Elk-1 is an important downstream target associated with activation of an SRE by E2. Both E2 (ERalpha-dependent) and growth factors (ERalpha-independent) activated the SRE in breast cancer cells via the Ras/MAPK pathway; however, in ER-negative CHO cells that do not express a receptor for TGF-alpha, only hormone-induced activation was observed in cells transfected with ERalpha.
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PMID:Estrogen receptor-mediated activation of the serum response element in MCF-7 cells through MAPK-dependent phosphorylation of Elk-1. 1114 55

Transactivation of the activation function-1 (AF-1) region of the estrogen receptor alpha (ER-alpha) gene is regulated by pathway "cross-talk" from Ras mitogen-activated protein kinase (MAPK). An analysis of this system is important for solving the problem of resistance to anti-estrogen agents used in the treatment of human breast cancer. We investigated the ER-alpha and Ras gene mutations and the MAPK-related protein status in 103 cases of breast carcinoma. None of the cases showed mutations in the AF-1 region of the ER-alpha gene. Despite the extremely low frequency of K- and H-Ras mutations in codon 12 (2/103 and 0/103), Ras p21 overexpression was identified in 29.1% (30/103), suggesting that the Ras activation in almost all cases we studied was not caused by point mutations but by enhanced expression. Our immunohistochemical analysis showed that the cases with overexpression of Ras and MAPK proteins (Ras p21, ERK-1, JNK-1, and p38) had a progressive tendency towards invasive growth, advanced-stage cancer, and decreased levels of ER-alpha protein. These results suggest that enhanced MAPK activity could be one of the characteristics of advanced breast cancer and that it could be involved in the transformation into estrogen-independent growth.
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PMID:Overexpression of mitogen-activated protein kinase superfamily proteins unrelated to Ras and AF-1 of estrogen receptor alpha mutation in advanced stage human breast cancer. 1115 22

Recent findings have established a connection between DNA methylation and transcriptionally inactive chromatin characterized by deacetylated histones. Because the absence of estrogen receptor alpha (ERalpha) gene expression has been associated with aberrant methylation of its CpG island in a significant fraction of breast cancers, we tested whether histone deacetylase activity contributes to the transcriptional inactivation of the methylated ER gene in a panel of ER-negative human breast cancer cells. Treatment of these cells with trichostatin A, a specific histone deacetylase inhibitor, led to dose- and time-dependent re-expression of ER mRNA as detected by reverse transcription-PCR without alteration in ERalpha CpG island methylation. Trichostatin A-induced ER re-expression was associated with increased sensitivity to DNase I at the ER locus in MDA-MB-231 cells. These data implicate inactive chromatin mediated by histone deacetylation as a critical component of ER gene silencing in human breast cancer cells. Therefore, histone deacetylation may be a potential target for therapeutic intervention in the treatment of a subset of ER-negative breast cancers.
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PMID:Transcriptional activation of estrogen receptor alpha in human breast cancer cells by histone deacetylase inhibition. 1115 87

Although several lines of epidemiological evidence suggest that estrogen exposure influences the incidence of breast cancer development, the mechanisms by which estrogen may stimulate the formation of breast cancer remain poorly understood. We have explored how alterations in estrogen exposure can influence the development of mammary cancer in the C3(1)/T(AG) transgenic model, where estrogen levels and estrogen receptor alpha (ERalpha) expression do not appear to modify the level of transgene expression. The C3(1)/T(AG) transgene becomes transcriptionally active in mammary ductal target cells at 3 weeks of age after the estrogen-induced differentiation of the mammary epithelial anlage to the ductal outgrowth stage. Complete maturation of the mammary ductal tree, however, is not required for cancer development because tumors arise in animals where ductal branching and terminal end bud formation have been prematurely arrested by ovariectomy. Mammary tumorigenesis in this model is promoted by increased estrogen exposure with the development of significantly more mammary intraepithelial neoplastic lesions and carcinomas associated with accelerated malignant conversion. The promotion of mammary tumors in this model appears to occur through an estrogen-induced proliferation and increase in the number of available target cells for transformation at the terminal ductal lobular units, as has been postulated to occur in women who receive hormone replacement therapy and/or by additional molecular mechanisms. We show, for the first time in a transgenic mouse model, that mammary tumor progression is associated with the loss of ERalpha expression, as has been often observed in human breast cancers with important clinical significance. Estrogen signaling may, therefore, serve different functions, depending upon the stage of tumorigenesis. ERbeta expression is up-regulated during tumor progression, although the functional significance of this remains to be determined.
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PMID:Estrogen promotes mammary tumor development in C3(1)/SV40 large T-antigen transgenic mice: paradoxical loss of estrogen receptoralpha expression during tumor progression. 1115 89


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