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 association between carcinoma of the breast and meningioma has been recognized recently. Three more cases are added to the few previously reported in the literature. An awareness of this association together with modern techniques of investigation, particularly CAT scanning, may permit earlier diagnosis and treatment of more cases. Meningioma as well as carcinoma of the breast is more common in women and the incidence of both tumors reaches a peak in the fifth and sixth decades. Both are related to pregnancy and have an estrogen-receptor protein. Lesions of the central nervous system following the diagnosis and treatment of breast cancer are usually presumed to be metastatic. Therefore, these lesions may be irradiated without complete clinical investigation. If the clinician is aware of this association, appropriate diagnostic procedures could lead to the surgical removal of a benign meningioma. Skull x-rays, bone scan, brain scan, CAT scan, and cerebral angiograms are useful in making a diagnosis. Besides surgery, radiation therapy and hormonal therapy may play a role in the management.
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PMID:Carcinoma of the breast and meningioma. Association and management. 683 59

In spite of pharmacokinetic studies, which have shown that only cis-DDP traces are found in brain tissue, cytotoxic activity of this drug in primary brain tumors has recently been reported. The purpose of our study was to examine whether cis-DDP aslo has antitumor properties in metastatic brain tumors. Twelve consecutive untreated patients with brain metastases recorded by CAT scans or radionuclide scans plus neurologic examinations underwent the treatment. Histology of primaries revealed 4 bronchial, 3 breast, 1 gastric, 2 colorectal carcinoma, 2 melanomas, and 1 soft tissue sarcoma. Cis-DDP was administered at the doses of 30 mg/m2 body surface daily for 4 days. All the patients were evaluated. Objective response (3 complete and 2 partial remissions) was observed in 5 of 12 patients (response rate 42%). Three stable disease cases were also noted; however, in the remaining 4 patients the disease in the brain progressed. Complete response (5 months) was observed in a breast cancer patient, in a melanoma (4+ months), and in a microcellular bronchial cancer (2+ months). Two partial responses (lung, breast) lasted 2+ and 2+ months. Toxicity was moderate but tolerable for the patients. The preliminary results of this study show that cis-DDP possesses antitumorigenic properties also in patients with metastatic brain tumors, which has not been proved till now.
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PMID:Preliminary report on antitumorigenic activity of cis-dichlorodiamine platinum in metastatic brain tumors. 719 35

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

We have investigated the control of vimentin expression in human breast cancer cell lines because of its transcriptional activation during malignant progression in breast cancer. Comparison of vimentin-positive (V+) and vimentin-negative (V-) breast cancer cell lines revealed several potential areas of vimentin gene regulation. Analysis of the chromatin structure of the vimentin gene in V+ and V- breast cancer cells showed DNase I hypersensitive sites in the 5' promoter region in V+ cell lines and 3' to the start of transcription in V- cell lines. Promoter deletion and reporter gene analysis revealed the importance of two adjacent AP-1 sites separated by seven GC-rich nucleotides for vimentin expression in V+ breast cancer cells. Mutational analysis of these sequences showed that although both AP-1 sites could bind nuclear proteins from V+ cells in vitro, one AP-1 site was sufficient to drive transcription in CAT reporter gene assays. The GC-rich spacer region had a modulating function on the activity of the AP-1 sites. In addition, levels of c-jun mRNA were elevated in V+ versus V- cells. In summary, distinct sites within the vimentin gene appear to be important for the control of vimentin expression in V+ and V- breast cancer cells with multiple elements acting coordinately to regulate vimentin expression.
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PMID:Regulation of vimentin gene transcription in human breast cancer cell lines. 798 48

The estrogen receptor (ER) is a hormone-regulated transcription factor which is thought to bind to specific DNA sequences as a homodimer. In order to better understand structural requirements for dimerization and its functional role in ER action, we synthesized a series of bivalent ligands based on the non-steroidal estrogen hexestrol. These molecular probes join two hexestrol molecules of the erythro (E, active) configuration with either 4 or 8 carbon linkers (designated E-4-E and E-8-E series, respectively), or with longer linkers comprised of ethylene glycol units (E-eg-E series). Several other bi- and monovalent control compounds were prepared. The bivalent ligands bind to ER with a relative affinity 1-7% that of estradiol. While most of the ligands demonstrated normal monophasic displacement curves in competitive binding assays with [3H]estradiol, uncharacteristic biphasic competitive binding curves were seen for some of the ligands, indicating possible structure-specific, negative site-site interaction. In ER-deficient Chinese hamster ovary (CHO) cells transfected with an expression vector encoding ER, one series of bivalent ligands (E-4-E) had little stimulatory activity and inhibited transcription stimulated by hexestrol, as determined by a transient transfection assay using an estrogen-responsive reporter gene construct [(ERE)2-TATA-CAT, containing two estrogen response elements linked to a TATA promoter and the chloramphenicol acetyl transferase reporter gene]. Monovalent or control bivalent ligands failed to antagonize hexestrol-stimulated activity and were as fully active as hexestrol itself. Studies performed in MCF-7 human breast cancer cells, which contain endogenous ER, yielded similar bioactivity profiles for the E-4-E bivalent inhibitory ligands, showing them to be effective estrogen antagonists, when using either induction of progesterone receptor or (ERE)2-TATA-CAT transcriptional activation as the endpoint. The E-8-E ligand, however, acted as a partial agonist/antagonist of ERE-reporter gene transactivation and a full agonist of progesterone receptor induction in MCF-7 cells, thus showing cell- and response-specific differences in the effects of this bivalent ligand. These bivalent ligands for ER do not show enhanced potency or receptor binding affinity; however, some of them display binding properties that suggest the possibility of structure-specific negative site-site interaction, and some of them function as quite effective estrogen antagonists.
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PMID:Bivalent ligands as probes of estrogen receptor action. 803 10

In addition to stimulation of the target gene fatty-acid synthetase, the synthetic progestin R5020 strongly inhibited estradiol-induced pS2 and cathepsin D mRNA levels in MCF7 human breast cancer cells as shown by Northern blot analysis. Inhibition was half-maximal with 30 pM R5020, and the antiprogestin RU486 had only a weak effect. Two human progesterone receptor isoforms have been described; isoform A is a truncated form of isoform B and lacks the 164 N-terminal amino acids. We hypothesized that the two isoforms could have a differential capacity to transrepress estrogen-induced responses. Therefore, in MDA-MB231 cells containing no progesterone and estrogen receptors, we transiently transfected progesterone receptor expression vectors coding for form B (hPR1 or hPR0) or form A (hPR2) along with the estrogen receptor expression vector HEO. We show that R5020 inhibited estradiol-induced transcription of the pS2-CAT reporter plasmid only in cells selectively expressing isoform B. The same results were obtained when progesterone receptor isoforms were overexpressed in MCF7, Ishikawa, HeLa, or NIH-3T3 cells. Transrepression was dependent on the promoter context since the extent of inhibition by isoform B was higher when evaluated with pS2 or cathepsin D nonpalindromic estrogen-responsive element-mediated transcription than with the perfect palindromic form of the vitellogenin gene. Isoform A was inefficient regardless of the reporter construct used. Inhibition varied with the isoform ratio, and isoform B had a dominant effect, with > 70% inhibition measured in cells transfected with the same amount of both progesterone receptor isoforms. Progestin repressed only one of the two transcription activation functions of the estrogen receptor, AF-2, which corresponds to the hormone-binding domain. We conclude that differential expression of progesterone receptor isoforms could be responsible for a tissue-specific inhibition of estrogen target genes by progestins.
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PMID:Differential effect of forms A and B of human progesterone receptor on estradiol-dependent transcription. 808

DNA from tumor tissue and peripheral blood lymphocytes of primary breast cancer patients was screened for the presence of p53 mutations. In DNA from one tumor we found that the histidine codon 193 (CAT) was somatically converted to arginine (CGT). This amino acid residue is highly conserved in many species, thus suggesting that such mutation plays an important role in the loss of wt-p53 function.
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PMID:A novel p53 mutant in human breast cancer revealed by multiple SSCP analysis. 818 56

In estrogen receptor positive human breast cancer cells, anti-estrogens inhibit the mitogenic effect of growth factors in the absence of estrogens. As activator protein-1 (AP-1) activity is one of the first nuclear events following growth factor receptor activation, we studied the effects of estrogens and anti-estrogens on growth factor-induced AP-1 activity using transient transfection of the AP-1-responsive gene (AP-1)4-TK-CAT into MCF7 cells. The growth factor-induced AP-1 response was increased by estradiol and inhibited by anti-estrogens in conditions where growth factor-induced c-fos and c-jun mRNA levels were unchanged by hormone and anti-hormone treatments. The same regulations were obtained when the AP-1 response was directly induced by co-transfection of c-fos and c-jun expression vectors. Co-transfection of the wild-type estrogen receptor HEGO amplified both effects. Inhibition of AP-1 activity by anti-estrogens was unlikely to be explained by the presence of residual estrogens in MCF7 cells. (i) anti-estrogens inhibited AP-1 activity in conditions where they had no effect on basal ERE-mediated activity levels, whereas estradiol was as efficient in stimulating both activities. (ii) The relative efficacy of the two anti-estrogens, OH-tamoxifen and ICI 164,384 in inhibiting these two activities was different; OH-tamoxifen was more efficient in inhibiting ERE-mediated activity, whereas ICI 164,384 was more efficient in trans-repressing AP-1-mediated activity. We conclude that in conditions where c-fos and c-jun syntheses were not affected, the estrogen receptor cooperated with growth factors to stimulate the AP-1 response when activated by estrogens but inhibited AP-1-mediated transcription when occupied by anti-estrogens.
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PMID:Estradiol increases and anti-estrogens antagonize the growth factor-induced activator protein-1 activity in MCF7 breast cancer cells without affecting c-fos and c-jun synthesis. 831 77

Retinoic acid (RA) strongly inhibits proliferation of the estrogen (E2)-dependent human breast cancer cell lines MCF7, T47D, and ZR75-1, but not the E2-independent and E2 receptor (ER)-negative lines MDA-MB231, MDA-MB468, BT20 and Hs578T. The specific sensitivity of the E2-dependent cell lines seems not to be caused by an inhibitory effect of RA on ER functioning since RA inhibited the proliferative response not only to E2 but also to insulin. Furthermore, endogenous RA receptors (RARs) hardly impaired transcriptional activation of an E2 responsive element-tk-CAT reporter construct. RAR alpha mRNA was highly expressed in the RA-responsive lines, but not in the unresponsive lines, except BT20. With the exception of Hs578T, also RAR beta mRNA expression was low in the unresponsive lines. While in the dependent lines and Hs578T RA activated RA responsive element-dependent transcriptional activity, this response was very low in MDA-MB231, MDA-MB468, and BT20, suggesting that the RA resistance of these latter three ER-negative lines is due to underexpression of functional RARs. Our results suggest that the loss of functional RARs may be a frequent event, leading to RA unresponsiveness of ER-negative breast cancer cells. This implies that both the steroid and retinoid receptor status of breast tumors may be used to predict a successful treatment with retinoids.
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PMID:Retinoic acid resistance of estradiol-independent breast cancer cells coincides with diminished retinoic acid receptor function. 838 11

The protein kinase A stimulator cAMP can potentiate the ability of progestins to induce the transactivation function of the human progesterone receptor (hPR). We questioned in the present study whether cAMP could functionally cooperate with the progestin antagonist RU486. In T47D human breast cancer cells, RU486 behaves as a pure antagonist with respect to induction of the progesterone-responsive mouse mammary tumor virus chloramphenicol acetyltransferase (MMTV-CAT) reporter gene. It fails to stimulate MMTV-CAT expression and completely inhibits induction by the synthetic progestin R5020. However, when RU486 is combined with 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP), MMTV-CAT is induced to levels approaching that stimulated by R5020 alone. Also, RU486 in the presence of 8-Br-cAMP is only partially effective in antagonizing R5020 action. The agonist activity exhibited under these conditions appears to be due to RU486 acting through hPR as evidenced by the fact that 8-Br-cAMP alone has no effect on MMTV-CAT, whereas induction by the combination of 8-Br-cAMP and RU486 is dose responsive to RU486 in a saturable manner and can be inhibited by the type I antiprogestin (prevents hPR-DNA binding) ZK98299, which does not exhibit positive functional cooperation with cAMP. Acquisition of agonist activity in the presence of 8-Br-cAMP also extends to the type II antiprogestin (permits hPR-DNA binding) ZK112993. Since RU486 is also a type II antagonist, these results suggest that detection of functional synergism between cAMP and antiprogestins may require binding of the hPR-antagonist complex to DNA. We propose that cross-talk between second messenger and steroid receptor signal transduction pathways may be one mechanism for resistance to steroid antagonists that frequently develops in breast cancer.
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PMID:The progesterone antagonist RU486 acquires agonist activity upon stimulation of cAMP signaling pathways. 838 50


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