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)

Previous reports have shown that progestins stimulate the proliferation of the human breast cancer cell line T47D in culture. Under different conditions other reports have shown progestin stimulation, inhibition or no effect on growth. It has also been shown that c-myc expression is stimulated at early times by progestins. We are currently testing the hypothesis that the mechanism of growth enhancement by progestins involves the stimulation of expression of c-myc. This hypothesis predicts a progesterone regulatory region in or near the c-myc gene. We have identified a region, from -2327 to -1833, which serves this function. This region includes a 15 bp sequence with homology to the PRE (progesterone response element) consensus sequence. Human progesterone receptor (PR) binds to this sequence in a specific, ligand-enhanced manner in electrophoretic mobility shift assays (EMSA). A 3507 bp HindIII-XbaI fragment of the 5' flanking region of the c-myc gene, -2327 to +1180, containing the progestin regulatory region and the c-myc promoter, confers progestin responsiveness to the CAT (chloramphenicol acetyl transferase) reporter gene in progesterone receptor (PR)-rich T47D human breast cancer cells, but not in PR-negative MDA-MB-231 cells. Removal of the progestin regulatory region abrogates progestin responsiveness. These data demonstrate that the sequence from -2327 to -1833 of the human c-myc gene includes a positive progestin regulatory region.
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PMID:A sequence in the 5' flanking region confers progestin responsiveness on the human c-myc gene. 940 78

Glutathione S-transferase P1 (GST P1-1) is normally expressed exclusively in estrogen receptor negative (ER-) but not receptor positive (ER+) cultured breast cancer cells. We examined the role of proximal promoter elements in GST P1 gene expression in MCF7 (ER+, GST P1-) and HS578T (ER-, GST P1+) breast cancer cells. Transient transfection of GST P1 promoter-CAT reporter genes confirmed that the GST P1 TRE (-69 to -60) and the adjacent distal GC box (-56 to -51) are required for basal promoter activity in both cell lines. Other studies identified differences in the GST P1 promoter activity and DNA-protein interactions between the two cell lines. Electrophoretic mobility shift assay revealed a protein-TRE interaction that is unique to nuclear proteins derived from GST P1 expressing HS578T cells. Furthermore, a putative silencer region contained within sequences -130 to -70 selectively reduced GST P1 promoter-CAT reporter gene expression in MCF7 but not HS578T cells. While this cell-line specific silencer contributed to the level of GST P1 promoter activity observed in the two cell lines, analysis of cells stably transfected with a novel genomic GST P1 minigene vector established that the silencer is insufficient to completely repress GST P1 transcription in ER+, MCF7 cells that do not normally express endogenous GST P1.
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PMID:Contribution of proximal promoter elements to the regulation of basal and differential glutathione S-transferase P1 gene expression in human breast cancer cells. 954 Aug 34

Polyamines are known to inhibit sequence specific DNA-binding activity of several zinc-finger transcription factors, including estrogen receptor (ER) binding to its cognate estrogen response element (ERE). The mechanism accounting for this disruption of protein-DNA interaction is unknown, although polyamine induction of DNA conformational changes has been suggested. To determine if polyamines can directly impair ER action, we compared the effects of putrescine (Putr), spermidine (Spd), and spermine (Spm) on ER DNA-binding (ER-ERE complex formation), ER ligand-binding (estradiol), ER structure (circular dichroism and sucrose gradient sedimentation), and the capacity of ER to transactivate an ERE-tk-CAT reporter in transient transfection assays. Polyamine concentrations causing 50% inhibition of ER-ERE formation (IC50 values) were found to be 1 mM for Putr, 4 mM for Spd, and 3 mM for Spm. This loss of ER DNA-binding was associated with a direct and irreversible effect on the ER DNA-binding domain (ER-DBD). Additionally, polyamines were observed to inhibit ER ligand-binding with IC50 values of 10 mM for Putr, 2 mM for Spd, and < 0.1 mM for Spm; and this correlated with a measureable change in higher-order ER structure (5S to 3.5S sedimentation) and inhibition of intracellular ER transactivation. These findings suggest that in ER-positive human breast tumors with increased polyamine (especially Spm) content, ER structure and function may be directly altered by tight-ion polyamine complexing that results in loss of ER-mediated gene regulation.
Breast Cancer Res Treat 1998 Apr
PMID:Polyamine inhibition of estrogen receptor (ER) DNA-binding and ligand-binding functions. 959 71

Normal breast tissue as well as most breast tumors are dependent on estrogen for growth. Breast tumors often progress to a hormone-independent state which is associated with poor prognosis. It has been proposed that activation of growth factor signaling pathways in the tumor cells may free them from hormonal control. Certain growth factors can mimic estrogen responses by activating the estrogen receptor via its phosphorylation by mitogen-activated protein (MAP) kinase. In this report, however, we show that fibroblast growth factor (FGF), despite activating MAP kinase, is growth-inhibitory for estrogen-dependent MCF-7 breast cancer cells. MCF-7 cells treated with FGFs exhibit slower growth than controls in both the presence and absence of estrogen, with a concomitant increase in the number of cells in G0/G1. Expression of a constitutively activated FGF receptor in these cells further decreases their growth rate, which is no longer influenced by FGF treatment. Activation of the FGF signaling pathway also reduces the induction of an estrogen-responsive CAT reporter plasmid by estrogen, an effect which appears to be independent of serine 118 in the estrogen receptor, a MAP kinase target site. The inhibitory effects of FGF are probably mediated through the sustained induction of the cyclin kinase inhibitor p21/WAF1/CIP1, which is upregulated at the mRNA and protein level by FGF. FGF treatment also results in the phosphorylation of STAT1. This upregulation of p21 and phosphorylation of STAT1 is not detectable in T47D breast cancer cells upon which FGF has no inhibitory effect.
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PMID:FGF signaling activates STAT1 and p21 and inhibits the estrogen response and proliferation of MCF-7 cells. 963 41

We compared the effect of estradiol on activator protein-1 (AP-1) activity in estrogen receptor positive (ER alpha+) and estrogen receptor negative (ER alpha-) human breast cancer cell lines transiently transfected with the AP-1-responsive reporter plasmid AP-1-TK-CAT and an ER alpha expression vector. While estradiol increased AP-1 activity in the ER alpha+ cell lines MCF7, ZR75.1, and T47D, it decreased (MDA-MB231 and BT20 cells) or had no significant effect (MDA-MB435 cells) on AP-1-mediated transcription in ER alpha- cells. Estradiol also inhibited AP-1 activity in ER alpha-MDA-MB231 cells stably transfected with ER alpha and in which ER alpha levels are close to those found in MCF7. Use of ER alpha mutant expression vectors demonstrated that the DNA-binding domain of ER alpha was needed for stimulation or inhibition of AP-1 activity by estradiol but suggested that ER alpha binding to estrogen-responsive elements was not required for these effects. Changes in regulation paralleled quantitative and qualitative changes in protein binding to AP-1 sites, as demonstrated by gel shift assay: protein binding was greater and DNA/protein complexes migrated faster for ER alpha--than for ER alpha+ cells. In fact, by Northern blot, a high level of Fra-1 mRNA was found in BT20 and MDA-MB231 cells as compared with ER alpha+ cells, and MDA-MB435 cells showed an intermediary level of expression. The differential expression of Fra-1 in MCF7 and MDA-MB231 cells was confirmed at the protein level by supershift experiments. In addition, overexpression of Fra-1 in MCF7 cells decreased the positive effect of estradiol while inhibition of Fra-1 expression in MDA-MB231 cells, by transient transfection of the Fra-1 antisense expression vector, abolished the negative effect of the hormone. In conclusion, we demonstrated that ER alpha- breast cancer cell lines differ from ER+ cells by a high level of AP-1 DNA-binding activity due, at least in part, to high Fra-1 constitutive expression. High Fra-1 concentration is crucial for the negative regulation of AP-1 activity by estradiol and thus may take part in estradiol-induced inhibition of cell proliferation in ER alpha- breast cancer cells transfected with ER alpha expression construct.
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PMID:FRA-1 expression level modulates regulation of activator protein-1 activity by estradiol in breast cancer cells. 965 2

Downregulation of MHC Class I antigens has been observed in many cancers and usually results from a decreased gene transcription. A reporter CAT gene dependent on the MHC Class I kappaB site or on a longer promoter is transactivated by NF-kappaB complexes containing p65 or RelB. p100 as well as IkappaB-alpha are potent inhibitors of this transcription and p100 sequesters RelB and p65 complexes in the cytoplasm of breast cancer cells. However, although p100 is highly expressed in a number of breast cancer cell lines, MHC Class I antigen expression was observed on all the cell lines we analysed and could be further induced by stimulation with the cytokines IFN-gamma or TNF-alpha. Stable transfection of a unresponsive mutated IkappaB-alpha Ser 32-36 expression vector showed that TNF-alpha induced MHC Cl I expression in an NF-kappaB-dependent way while IFN-gamma did it independently of any NF-kappaB activation.
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PMID:Regulation of major histocompatibility complex class I expression by NF-kappaB-related proteins in breast cancer cells. 968 29

Under acidic conditions, indole-3-carbinol (13C) is converted to a series of oligomeric products thought to be responsible for the biological effects of dietary 13C. Chromatographic separation of the crude acid mixture of 13C, guided by cell proliferation assay in human MCF-7 cells, resulted in the isolation of 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr-1) as a major antiproliferative component. LTr-1 inhibited the growth of both estrogen-dependent (MCF-7) and -independent (MDA-MB-231) breast cancer cells by approximately 60% at a non-lethal concentration of 25 microM. LTr-1 had no apparent effect on the proliferation of MCF-7 cells in the absence of estrogen. LTr-1 was a weak ligand for the estrogen receptor (ER) (IC50 70 microM) and efficiently inhibited the estradiol (E2)-induced binding of the ER to its cognate DNA responsive element. The antagonist effects of LTr-1 also were exhibited in assays of endogenous pS2 gene expression and in cells transiently transfected with an estrogen-responsive reporter construct (pERE-vit-CAT). LTr-1 activated both binding of the aryl hydrocarbon (Ah) receptor to its cognate DNA responsive element and expression of the Ah receptor-responsive gene CYP1A1. LTr-1 was a competitive inhibitor of CYP1A1-dependent ethoxyresorufin-O-deethylase (EROD) activity. In summary, these results demonstrated that LTr-1, a major in vivo product of I3C, could inhibit the proliferation of both estrogen-dependent and -independent breast tumor cells and that LTr-1 is an antagonist of estrogen receptor function and a weak agonist of Ah receptor function.
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PMID:Cytostatic and antiestrogenic effects of 2-(indol-3-ylmethyl)-3,3'-diindolylmethane, a major in vivo product of dietary indole-3-carbinol. 1044 93

Medroxyprogesterone acetate (MPA), which is frequently used as second line hormonal therapy for the treatment of metastatic breast cancer, binds with high affinity to the progesterone receptor (PR). However, the androgenic side-effects of MPA suggest that it may also activate androgen receptor (AR) regulated pathways. Treatment of the human breast cancer cell lines MDA-MB-453, ZR-75-1 and T47-D with high dose (100 nM) MPA resulted in 26-30% inhibition of cell growth, which was partially reversed by co-treatment with a 10-fold excess of the synthetic antiandrogen, anandron. Scatchard analysis demonstrated specific, high affinity (non-PR) binding of [3H]MPA to cytosols prepared from the PR-/AR+ MDA-MB-453 and PR+/AR+ ZR-75-1, but not the PR-/AR- BT-20 breast cancer cell lines. Competition of [3H]MPA binding to MDA-MB-453 cytosols by equimolar concentrations of androgens (5alpha-dihydrotestosterone (DHT), R1881) and the antiandrogen, anandron was consistent with binding of MPA to the AR. In ZR-75-1 cell cytosol fractions, DHT, R1881 and anandron only partially competed out [3H]MPA binding, suggesting that androgens displace [3H]MPA binding to AR but not to PR. Induction by MPA of AR transactivation was demonstrated in MDA-MB-453 and ZR-75-1 cells, and in the CV-1 cell line transfected with a full-length AR. In these cell lines the increased activity of the androgen responsive reporter gene (MMTV-CAT) by 1 nM MPA was fully (MDA-MB-453, CV-1) or partially (ZR-75-1) inhibited by co-culture with 1 microM anandron. These findings indicate that MPA is an AR agonist and suggest that the in vivo effects of MPA in breast cancer patients may in part be mediated by the AR.
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PMID:Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells. 1050 95

The MUC1 gene encodes a mucin glycoprotein and is overexpressed in breast cancer. Knowledge of the mechanisms leading to MUC1 overexpression may help in the development of molecular approaches for breast cancer therapy. In order to study the regulation of the MUC1 gene transcription, we analyzed functional activities of various deletion mutants of the MUC1 promoter. We established that transcriptional cis-elements present in the SacI/XmnI fragment of the promoter are competent and sufficient for expression of, at least, tandem repeats containing isoform(s) of the MUC1 protein. CAT transfection analysis showed that both the 3' and 5' regions of the SacI/XmnI fragment possess transcription activities. Promoter activities associated with the SacI/XmnI fragment were confirmed by a RNase protection assay, which demonstrated multiple transcription start sites (TSSs) in the MUC1 gene transcribed in epithelial T47D cells. We show that treatment of the T47D cells with TGFbeta1 leads to activation of additional TSSs in the MUC1 gene. The roles of the structural and functional properties of the MUC1 promoter in MUC1 gene transcription are discussed.
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PMID:Analysis of the promoter of the MUC1 gene overexpressed in breast cancer. 1056 95

This report describes an investigation of the role of 1, 25-dihydroxyvitamin D (VD(3)) in the regulation of estrogen receptor-alpha (ER) in the ER-positive breast cancer cell line, MCF-7. Treatment of cells with 10 nM VD(3) resulted in a 50% decline in the concentration of ER protein at 24 h. Scatchard analysis showed a corresponding decrease in the number of estradiol binding sites and no alteration in the binding affinity of estradiol for the ER (K(d) = 0.08 nM in VD(3)-treated cells compared with K(d) = 0.07 nM in control cells). Vitamin D treatment also caused a 50% decrease in the steady state amount of ER mRNA, which was maximal by 18 h. In vitro transcription run-on experiments demonstrated a decrease of approximately 60% in transcription of the estrogen receptor gene. Transient transfections using an ER promoter-CAT construct also demonstrated a 40% decrease in CAT activity after VD(3) treatment. Sequence analysis identified a potential vitamin D response element (nVDRE) within the ER promoter. When this element was mutated, the ability of VD(3) to block transcription from the ER promoter was lost. When the nVDRE was placed upstream of a heterologous promoter, nVDRE-SV40-CAT, treatment with VD(3) resulted in a 50% decrease in CAT activity. Interestingly, co-transfection of either the ER promoter-CAT or the nVDRE-SV40-CAT construct and a vitamin D receptor expression vector into COS-1 or CV-1 cells showed an approximately 4-fold increase in CAT activity after VD(3) treatment. Taken together these data suggest that VD(3) inhibition of ER gene transcription is mediated through a nVDRE in the ER promoter. Inhibition appears to be cell specific.
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PMID:Regulation of estrogen receptor-alpha gene expression by 1, 25-dihydroxyvitamin D in MCF-7 cells. 1057 47


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