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)

Under normal cellular conditions, human progesterone receptors (PR), immune-isolated from cytosols of T47D breast cancer cells, associate with two heat shock proteins (hsps), hsp 90 and hsp 70. Receptors activated by hormone binding in vivo and extracted from nuclei with 0.5 M NaCl no longer associate with hsp 90 but retain association with hsp 70. We have examined the effect of heat shock treatment of cells on hsp-receptor interactions and on receptor function. Heat shock resulted in a partial reduction in cellular levels of PR, but receptors that remained were functional for both steroid and DNA binding activities. By steady-state [35S]methionine labeling prior to heat shock treatment, it was determined that heat shock did not affect the composition or maintenance of preexisting cytosolic PR.hsp 90.hsp 70 complexes. By contrast, immune isolation of PR complexes from cells pulse-labeled with [35S]methionine showed that heat shock altered the composition of newly synthesized hsps associated with PR. After heat shock, both the highly inducible form of hsp 70 (72K hsp) and a 100K hsp were bound to cytosol PR, and inducible 72K hsp remained bound with the nuclear-activated PR. Neither of these hsps were associated in detectable amounts with PR under normal cellular conditions. With respect to receptor function, heat shock treatment substantially enhanced the activity of PR in vivo as determined by measuring hormone-dependent PR-mediated transcription of a target reporter gene (MMTV-CAT) that was stably transfected into T47D cells. Heat shock treatment alone, in the absence of hormone, did not stimulate MMTV-CAT expression nor did it affect transcription from a control reporter gene, pSV2-CAT, suggesting that enhanced receptor activity was due to an effect on PR-mediated processes and not to a general effect on transcription. Induction of the heat shock response by a related chemical stress (sodium arsenite) also enhanced PR activity in vivo. Interestingly, sodium arsenite produced both a greater induction of hsp 90 and hsp 70 synthesis and a greater fold enhancement of PR-mediated gene transcription than did heat shock. This suggests that enhancement of PR activity is related not only to induction of hsp synthesis but also to the severity of the stress response. The present results provide an indication that in certain cells there may exist an interrelationship between the activation pathways by which cells respond to stress and to steroid hormones. Possible mechanisms responsible for heat shock effects on PR activity are discussed.
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PMID:Heat shock alters the composition of heteromeric steroid receptor complexes and enhances receptor activity in vivo. 131 48

Human selenium-dependent glutathione peroxidase (hGPx1) (EC 1.11.1.9) is thought to be involved in many critical cellular functions as a result of its role in glutathione-mediated reduction of toxic peroxides, and it is implicated as a mechanism of resistance against oxygen free radicals. Previous studies have demonstrated that the gene encoding hGPx1 (hgpx1) is more highly expressed in multidrug-resistant AdrR MCF-7 human breast cancer cells than in the parental WT MCF-7 cell line. In order to further study the transcriptional regulation of hgpx1, we have cloned the genomic hgpx1 gene and determined its nucleotide sequence. The 2550-base pair (bp) 5'-flanking sequence of hgpx1 contained the terminal 511 bp of the 3' end of a previously reported rhoH12 cDNA (Yeramian, P., Chardin, P., Madaule, P., and Tavitian, A. (1987) Nucleic Acids Res. 15, 1989), a ras-related oncogene. Further downstream from rhoH12, but before the start of transcription of hgpx1, RNase protection analysis revealed a transcribed sequence of at least 270 bp which we have called mid. RNA transcripts homologous to both rhoH12 (1.8 and 1.5 kilobase pairs (kb)) and mid (1.8 kb) are also more highly expressed in AdrR MCF-7 cells than in WT MCF-7 cells. We screened an AdrR MCF-7 cDNA library with the mid sequence and isolated a partial cDNA clone which contains both mid and rhoH12 sequences and is colinear with the genomic sequence which extends from 10 bp 3' to the rhoH12 stop codon to 810 bp 5' to the start of transcription of hgpx1. The start of transcription of hgpx1 in AdrR MCF-7 cells was determined by primer extension analysis. The promoter and 2 kb of the 5'-flanking sequence of hgpx1 was fused to the bacterial chloramphenicol acetyltransferase gene (hGPx1-CAT1). Analysis of deletion constructs of hGPx1-CAT1 revealed three possible cis-acting regulatory regions. The transcriptional regulation of hgpx1 was examined using the hGPx1-CAT hybrid genes and nuclear run-on studies. We found no evidence that increased mRNA transcript formation could account for different levels of hgpx1 RNA either in different breast cancer cell lines or in response to selenium.
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PMID:Structure and function of the 5'-flanking sequence of the human cytosolic selenium-dependent glutathione peroxidase gene (hgpx1). 155 8

The glutathione S-transferase pi gene (GST pi) is highly expressed in estrogen receptor negative (ER-) but not expressed in ER+ human breast cancer cell lines. To define regulatory mechanisms of GST pi gene expression, we analyzed both the activity of the GST pi promoter and the posttranscriptional fate of GST pi RNA sequences in three ER+ and three ER- breast cancer cell lines. Expression of a transiently transfected CAT reporter gene driven by the GST pi promoter and 2203 nucleotides of 5'-flanking sequences were similar in all six cell lines regardless of ER status. Endogenous GST pi transcription rates in nuclei isolated from ER- cells were quite low despite high steady state levels of cytoplasmic mRNA. Furthermore, the endogenous GST pi gene was transcribed in ER+ nuclei at rates similar to those obtained in ER- nuclei. We determined the stabilities of mRNAs transcribed from the endogenous GST pi gene (ER- cells) and from a stably transfected GST pi cDNA expression vector (ER+ and ER- cells). The endogenous GST pi mRNA was extraordinarily stable in ER- cells. Comparisons between transfected ER+ and ER- cells revealed no significant differences in the stabilities of transfection-derived GST pi mRNA sequences. We conclude that GST pi mRNA stability contributes significantly to the high levels of cytoplasmic mRNA observed in ER- cells, but that the differential expression of GST pi in ER+ versus ER- cells is governed by other posttranscriptional processes.
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PMID:Posttranscriptional control of glutathione S-transferase pi gene expression in human breast cancer cells. 158 35

Studies on estrogen receptor (ER)-positive human breast cancer cell lines have shown that estrogen treatment positively modulates the expression of the genes encoding transforming growth factor-alpha (TGF alpha), 52-kDa cathepsin-D, and pS2. To determine whether these genes would be similarly regulated by estrogens in normal human mammary epithelial cells, we stably transfected immortal nontumorigenic human mammary epithelial cells with an ER-encoding expression vector. ER-negative tumor cells were also transfected for comparison. Levels of TGF alpha and 52-kDa cathepsin-D mRNA were enhanced by estrogen treatment of both ER-transfected immortal and tumorigenic cells, demonstrating that the ER by itself is sufficient to elicit estrogenic regulation of the expression of these genes. In contrast, expression of the pS2 gene was detected only in the ER-transfected tumor cells. The ER in both cell lines is capable of recognizing the pS2 promoter, however, since estrogen enhanced the activity of an introduced pS2-CAT reporter plasmid in transient expression analyses. These and other experiments with somatic cell hybrids between the immortal cells and ER+/pS2+ MCF-7 tumor cells, where pS2 gene expression is extinguished, support the conclusion that the immortal nontumorigenic cells encode gene products that block endogenous pS2 expression. These results also imply that such repressors are not active in the tumor cells.
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PMID:Induction of estrogen-regulated genes differs in immortal and tumorigenic human mammary epithelial cells expressing a recombinant estrogen receptor. 166 44

The emergence of resistant cells reduces the efficacy of many forms of drug therapy in human breast cancer. In order to understand some of the possible mechanisms by which hormonally dependent human breast cancers develop resistance to progestin therapy we have developed a human breast cancer cell line (5-RP) which is resistant to the growth inhibitory effects of progestins in culture. These cells routinely grow in 10 microM medroxyprogesterone acetate (MPA). The cell line was developed from T-47D-5 human breast cancer cells by stepwise selection in increasing concentrations of MPA. The progestin-resistant phenotype was relatively stable as assessed by the removal of MPA from the medium for varying periods of time. 5-RP cells passaged in the absence of MPA were still essentially insensitive to the growth inhibitory effects of MPA for at least 22 passages. Even at 53 passages out of the drug the 5-RP line was still less sensitive than the original T-47D-5 parent line. Transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF) receptor mRNA were both increased in the 5-RP line compared to the T-47D-5. Consistent with increased TGF-alpha expression, the EGF receptor measured by ligand binding was decreased. When the cells were removed from MPA, TGF-alpha expression declined gradually, but EGF-receptor mRNA levels increased, as did EGF-binding activity. These cells remained estrogen and progesterone receptor positive. Although progestins did not downregulate estrogen receptor expression, they did downregulate progesterone receptor expression in the 5-RP line. The progesterone receptor level of the 5-RP line, in the absence of MPA, was approximately 58% of that found in T-47D-5 cells, even after MPA had been removed for long periods of time. This decrease in receptor level was reflected in decreased ability to respond to progestins as assessed by the decreased ability of MPA to activate expression of both an endogenous gene (EGF receptor) as well as a transiently transfected progestin-responsive gene (MMTV-TK-CAT). Progestin resistance in the 5-RP cell line appears to be multifactorial, involving both increased growth factor expression and decreased receptor levels. It is likely, however, that these two aspects do not account entirely for the progestin-resistant phenotype and as yet other unidentified mechanisms may also be involved.
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PMID:Mechanisms involved in the evolution of progestin resistance in human breast cancer cells. 184 41

RU486 induced the binding to a palindromic progestin responsive element (PRE) in vitro of homo- and heterodimers of the human progesterone receptor (hPR) isoforms A and B, present in T47D breast cancer cells or in HeLa cells transiently expressing the recombinant proteins. The resulting complexes were indistinguishable from those induced with the agonist R5020 with respect to specificity, affinity and stability. Ligand exposure was a necessary prerequisite to observe PR/PRE complexes. Antagonist-induced complexes migrated more rapidly during electrophoresis than agonist-induced ones, and no 'mixed' PR/RU486-PR/R5020 complexes were observed, suggesting that the dimerization interfaces of agonist- and antagonist-bound molecules are non-compatible. The analysis of a series of deletion mutants and chimeric receptors revealed the presence of two transcription activation functions (TAFs), located in the N-terminal region A/B (TAF-1) and the hormone binding domain (TAF-2). In the presence of agonists, both TAFs were active in HeLa cells. In the presence of RU486 TAF-2 was inactive, while TAF-1 within the hPR form B/RU486 complex activated transcription from a reporter gene containing a single palindromic PRE. We consider this to be the most convincing evidence that the receptor/RU486-complex does in fact bind to PREs in vivo. No transcriptional activation was observed in the presence of RU486 from a reporter gene containing the complex MMTV-LTR PRE. In contrast to hPR form B, form A was not able to activate transcription from PRE/GRE-tk-CAT in the presence of RU486. In vivo competition between hPR/RU486 and either cPR/R5020 or the human glucocorticoid receptor/dexamethasone (hGR/Dex) complex further supported that hPR/RU486 bound in vivo to its cognate responsive element. Indeed, the observed inhibition of transcription was shown to be due to competition for the MMTV PRE, since no transcriptional interference by the hPR/RU486 was observed, and since no heterodimers were formed between hPR/RU486 and cPR/R5020 or hGR/Dex. That the ligand-free hPR, however, was unable to compete, demonstrated that ligand binding is the prerequisite for DNA binding of hPR in vivo.
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PMID:Agonistic and antagonistic activities of RU486 on the functions of the human progesterone receptor. 224 58

The precursor of cathepsin D, a lysosomal acidic protease, is secreted by human breast cancer cells, where its synthesis is specifically induced by estrogens and growth factors. In this study, we investigated the hormonal regulation of cathepsin D and its mRNA in uterine cells. In the Ishikawa endometrial cancer cell line, epidermal growth factor (EGF) increased the level of cathepsin D and its mRNA 2- to 3-fold. Although expression of the transiently transfected estrogen-responsive recombinant (Vit. tk. CAT) and the endogenous progesterone receptor was markedly increased by estradiol in Ishikawa cells, estradiol did not alter the level of cathepsin D or its mRNA. The progestin R5020 induced the expression of the LTR sp65 CAT, which contains the progesterone-responsive element of the MMTV but it too was without effect on cathepsin D. By contrast, the expression of cathepsin D gene, in normal rat uterus, was increased by R5020 but not by estradiol. We conclude that cathepsin D gene expression is regulated differently by sex steroid hormones in endometrial and breast cancer cell lines, whereas it is similarly induced by EGF in these cells.
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PMID:Differential regulation of cathepsin D by sex steroids in mammary cancer and uterine cells. 261 33

We have investigated the influence of the 5'-flanking region of the chicken lysozyme gene on steroid dependent gene expression. By transient transfection of lysozyme-CAT fusion genes into the human breast cancer cell line T-47D, a DNA element was identified which stimulates CAT expression when transfected cells are treated with progesterone. This element is distinct from a second hormone responsive element (HRE) located in the lysozyme promoter region; it activates the lysozyme and the TK promoter, irrespective of orientation and distance, and is therefore referred to as hormone responsive element on its own. The location of this newly discovered HRE between -2250 and -1815 relative to the transcriptional start site, corresponds to the position of a steroid inducible DNase I-hypersensitive site in chromatin of oviduct cells. This observation suggests a physiological role for the upstream element. In vitro DNase I protection experiments revealed six binding sites for both progesterone and glucocorticoid receptors within the sequences of the upstream HRE. The three distal binding sites are not required for hormonal stimulation of the TK promoter, while the three proximal binding sites, which are contiguously arranged, work in a cooperative manner.
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PMID:A progesterone responsive element maps to the far upstream steroid dependent DNase hypersensitive site of chicken lysozyme chromatin. 341 33

Pulmonary dissemination of breast cancer is frequent in those patients who have died of the disease and in those survivors who have not been cured after removal of the breast and X-ray treatment in the advanced states of the disease. When the metastases are identified, they are almost always multiple and bilateral. The appearance of a solitary, late pulmonary coin lesion (metachrone) in someone with breast cancer certainly suggests a pulmonary metastasis, but in fact, it is more likely to be a second cancer than a metastasis, that is, a primary bronchopulmonary cancer. The presence of a solitary pulmonary coin lesion in someone who has or who has had breast cancer, presents therefore certain particular problems. After having controlled by xerotomography or CAT that there is no pulmonary diffusion in either lung, that there is no invasion of other tissues or organs, and after having controlled locally around the breast cancer, then it is imperative to remove the lesion without delay since it is certainly malignant and most probably a second cancer, that is a primary broncho-pulmonary cancer, an adenocarcinoma, detected at an asymptomatic stage. the prognosis of a broncho-pulmonary adenocarcinoma, depends on the precocity of its removal.
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PMID:[Surgical treatment of pulmonary round foci detected in one male and eight female patients with breast cancer. Solitary metastasis, a second primary bronchopulmonary cancer or benign round foci? (author's transl)]. 624 93

The aim of this study was to examine antitumorigenic Cis DDP properties in metastatic brain tumors. Thirty-four untreated patients with brain metastases recorded by CAT scans or radionuclide scans plus neurological examinations underwent the treatment. Pathohistology of primary tumors mainly showed breast [8] and lung [8] carcinomas and melanomas [10]. Other localizations of primary tumors were infrequent. Cis DDP was administered in doses of 30 mg/m2 body surface daily over 4 days. All the patients received at least two cycles and 33 have been evaluated. No corticosteroids were administered concurrently. An objective response (seven complete and seven partial remissions) was observed in 14 out of 33 patients (42%). Six stable disease cases were also noted. A complete response (5-14 months) was observed in breast cancer [4], lung cancer [1], and melanoma [2]. Seven partial responses lasted 2-5 months. Antitumorigenic activity of Cis DDP was also noted in extracerebral tumor lesions, especially in breast cancer patients. Toxicity was moderate but tolerable. The results of this study have shown Cis DDP to possess antitumorigenic properties also in patients with metastatic brain tumors, a point that has not been proved so far.
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PMID:Phase II clinical trial of cis dichlorodiammine platinum (Cis DDP) in metastatic brain tumors. 676 44


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