Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0276241 (MCF)
 28,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aromatase is present in human breast tumors and in breast cancer cell lines suggesting the possibility of in-situ estrogen production via the androstenedione to estrone and estradiol pathway. However, proof of the biologic relevance of aromatase in breast cancer tissue requires the demonstration that this enzyme mediates biologic effects on cell proliferation. Accordingly, we studied the effects of the aromatase substrate, androstenedione, on the rate of proliferation of wild-type and aromatase-transfected MCF-7 breast cancer cells. Androstenedione did not increase cell growth in wild-type MCF-7 cells which contained relatively low aromatase activity and produced 4-fold more estrone than estradiol. In contrast, aromatase-transfected cells contained higher amounts of aromatase, produced predominantly estradiol, and responded to androstenedione with enhanced growth. An aromatase inhibitor fadrozole hydrochloride, blocked the proliferative effects of androstenedione providing evidence for the role of aromatase in this process. As further evidence of the requirement for aromatase, cells transfected with the neomycin resistance expression plasmid but lacking the aromatase cDNA did not respond to androstenedione. These studies provide evidence that aromatase may have a biologic role for in-situ synthesis of estrogens in breast cancer tissue.
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PMID:Effect of androstenedione on growth of untransfected and aromatase-transfected MCF-7 cells in culture. 847 72

Human endometrial and breast carcinoma cell lines were examined for aromatase activity and the effects of sex steroids (estradiol and testosterone) on DNA synthesis. Aromatase activity was high (greater than 500 fmol/10(7) cells/24 h) in the cell lines MCF-7 and OMC-2, moderate (100-499 fmol/10(7) cells/24 h) in the cell lines HEC-59 and Ishikawa, and low (less than 100 fmol/10(7) cells/24 h) in the HHUA cell line. A substantial stimulation of DNA synthesis by estradiol (10(-9)M) was observed in cell lines HEC-59, OMC-2, and MCF-7, with an increase in [3H]thymidine uptake of over 250%. The Ishikawa cell line was stimulated moderately (115-249%). No estradiol-induced increase in DNA synthesis was observed in HHUA. Responsiveness of DNA synthesis to testosterone was observed in cell lines that showed the greatest response to estradiol, namely HEC-59, OMC-2, and MCF-7. Otherwise, estrogen-responsiveness did not always correlated with a significant aromatase activity. These data suggest that some but not all endometrial carcinomas may possess an aromatase-dependent growth stimulating system.
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PMID:Aromatase activity and the effect of estradiol and testosterone on DNA synthesis in endometrial carcinoma cell lines. 847 79

In our previous study we found that MCF-7 cells possess aromatase activity and stimulate estrogen receptor-mediated growth. The pathways through which androgens are converted to estrogens by aromatase and estrogens interact with estrogen receptors contribute significantly to growth stimulation. The administration of aromatase inhibitor results in suppression of growth stimulation by androgens. This system enabled us to assess directly the biological activities of aromatase inhibitors. Aromatase activity was inhibited in a dose-dependent manner by the addition of aminoglutethimide and CGS 16949A, competitive inhibitors, and of 14 alpha-hydroxy-4-androstene-3,6,17-trione and 4-hydroxy-androstenedione, mechanism-based inhibitors. After preincubation with mechanism-based inhibitors, aromatase activity was significantly suppressed, whereas after preincubation with competitive inhibitors, it was adversely increased. These effects were concentration- and time-dependent. Preincubation with competitive inhibitors resulted in augmentation of subsequent androgen stimulation of thymidine incorporation, while preincubation with mechanism-based inhibitors resulted in diminished stimulation by subsequent androgen administration. These results suggest that in MCF-7 cells competitive inhibitors adversely induce aromatase and accelerate the subsequent androgen stimulation of DNA synthesis. Suicide inhibitors are more effective than competitive inhibitors. This system will be useful for aromatase inhibitor screening.
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PMID:Growth suppression of MCF-7 human breast cancer cells by aromatase inhibitors: a new system for aromatase inhibitor screening. 847 80

While hormone-dependent, mammary tumors induced with carcinogens (DMBA or NMU) in intact rats have been used extensively for studying aromatase inhibitors, there is currently no suitable model to investigate their effects in human breast cancers in vivo. While hormone responsive tumors can be formed in the athymic mouse using human breast carcinoma MCF-7 cells, due to the low ovarian estrogen production, tumor growth is induced with estradiol supplementation. Thus, this model is unsuitable for studies of aromatase inhibitors. We have induced tumors without the need for estrogen supplementation by co-inoculating MCF-7 cells with Matrigel, a basement membrane preparation, into intact athymic mice. In one experiment, 45 days after inoculation, mice were assigned to the control group or 4-hydroxyandrostenedione (4-OHA) (1 mg/day s.c.) treatment for 52 days. Tumor volumes in the control mice increased 672%, whereas tumor volumes in the treated mice did not change significantly (178.9 +/- 16.2 to 336.6 +/- 120 mm3). In the second experiment, 55 days after inoculation, groups of mice were treated with the antiestrogen, tamoxifen (5 micrograms/day s.c.) or vehicle (controls). Tumor volumes in the control mice increased 325% in 58 days, whereas there was no significant change in tumor volume in the tamoxifen treated group (338.8 +/- 55.3 to 330.6 +/- 84.9 mm3). The results suggest that (1) the tumors resulting from MCF-7 cells co-inoculated with Matrigel are estrogen-dependent and (2) tamoxifen and 4-OHA were effective in suppressing growth of these tumors. The results suggest that this model should be useful for evaluating the effects of aromatase inhibitors and for comparing breast cancer treatments.
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PMID:MCF-7 human breast carcinomas in nude mice as a model for evaluating aromatase inhibitors. 847 81

Metastatic prostate adenocarcinoma is a leading cause of cancer-related deaths among men. First line treatment is primarily aimed at blocking the synthesis and action of androgens. As primary endocrine treatment, androgen deprivation is usually achieved by orchidectomy or LHRH analogues, frequently combined with androgen receptor antagonists in order to block the residual adrenal androgens. However, nearly all the patients will eventually relapse. Available or potential second line therapies include, among others, alternative endocrine manipulations and chemotherapy. Cytochrome P450-dependent enzymes are involved in the synthesis and/or degradation of many endogenous compounds, such as steroids and retinoic acid. Some of these enzymes represent suitable targets for the treatment of prostate cancer. In first line therapy, inhibitors of the P450-dependent 17,20-lyase may achieve a maximal androgen ablation with a single drug treatment. Ketoconazole at high dose blocks both testicular and adrenal androgen biosynthesis but its side-effects, mainly gastric discomfort, limit its widespread use. A series of newly synthesized, more selective, steroidal 17,20-lyase inhibitors related to 17-(3-pyridyl)androsta-5,16-dien-3beta-ol, may open new perspectives in this field. In prostate cancer patients who relapse after surgical or medical castration, therapies aiming at suppressing the remaining adrenal androgen biosynthesis (ketoconazole) or producing a medical adrenalectomy (aminoglutethimide+hydrocortisone) have been used, but are becoming obsolete with the generalization of maximal androgen blockade in first line treatment. The role of inhibition of aromatase in prostate cancer therapy, which was postulated for aminoglutethimide, could not be confirmed by the use of more selective aromatase inhibitors, such as formestane. An alternative approach is represented by liarozole fumarate (LIA), a compound that blocks the P450-dependent catabolism of retinoic acid (RA). In vitro, it enhances the antiproliferative and differentiation effects of RA in cell lines that express RA metabolism, such as F9 teratocarcinoma and MCF-7 breast carcinoma cells. In vivo, monotherapy with LIA increases RA plasma levels and, to a greater extent, endogenous tissue RA levels leading to retinoid-mimetic effects. In the rat Dunning prostate cancer models, it inhibits the growth of androgen-independent as well as androgen-dependent carcinomas relapsing after castration. Concurrently, changes in the pattern of cytokeratins characteristic of increased differentiation were observed. Early clinical trials show that LIA, in second or third line therapy in metastatic prostate cancer, induces PSA responses in about 30% of unselected patients. In some patients regression of soft tissue metastasis ha been observed. In a subgroup of patients, an important relief of metastatic bone pain was also noted.
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PMID:P450-dependent enzymes as targets for prostate cancer therapy. 860 34

Aromatase, a cytochrome P450, catalyzes three consecutive hydroxylation reactions converting C19 androgens to aromatic C18 estrogens. In this study, the regulatory properties of a 696-base pair region, that contains the promoter II and is situated immediately upstream of exon II of the human aromatase gene, were investigated. Chloramphenicol acetyltransferase (CAT) functional studies with DNA segments derived from this genomic region and primer-extension analysis revealed the presence of a second promoter which is functional in adipose stromal cells and in breast cancer cells. Detailed DNase-1 footprinting analysis, DNA mobility shift assays, and CAT functional studies of this genomic region were performed and led to the identification of a segment (B1) that could act as a promoter (probably promoter I.3) in adipose stromal and breast cancer cells. The study revealed further that the B1 region could be divided into two domains which were designated RE1 and RE2. RE1 was found to have the promoter activity, and RE2 was found to regulate the promoter activity of RE1, but in different manners in MCF-7 cells (as an example of breast cancer cells) and in adipose stromal cells. RE2 was found to function as a positive regulatory element in MCF-7 cells and as a negative regulatory element in adipose stromal cells, respectively. DNA mobility shift and UV-cross-linking experiments with BrUrd-substituted B1 fragment and nuclear extracts isolated from two types of cells were performed. The experiments identified DNA-bound proteins with molecular masses around 50 kDa. These findings serve as the basis for further examination of the regulatory mechanism of aromatase expression in human breast cancer and adipose stromal cells.
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PMID:Identification of a promoter that controls aromatase expression in human breast cancer and adipose stromal cells. 866 88

The levels of the aromatase gene and its expression in MCF-7 human breast cancer cells and seven additional cultured cells were investigated. Using normal human foreskin fibroblasts as the control, the aromatase gene appeared to be amplified in MCF-7 cells as shown by Southern and DNA slot blot analyses utilizing human placental aromatase cDNA as the probe. However, the promoter I.1 and the first exon of the aromatase gene were not amplified in MCF-7 cells based on results obtained from DNA slot blot analysis using oligonucleotide probes having sequences derived from those regions of human aromatase gene. Aromatase was expressed at a very low level in this cell line as indicated by Northern blot analysis to measure the level of aromatase mRNA, immunoprecipitation analysis to measure the level of aromatase protein, and aromatase activity measurement. Furthermore, nucleotide sequence analysis of the aromatase cDNA obtained from MCF-7 cells by PCR techniques, revealed no sequence difference from that of the enzyme expressed in placenta. These results lead us to conclude that the expression of aromatase in MCF-7 cells is under the control of an unusual promoter and aromatase gene expression is repressed at the transcriptional level in these cells.
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PMID:Aromatase gene is amplified in MCF-7 human breast cancer cells. 866 62

The proliferation of MCF-7, human breast cancer cell line, was stimulated by testosterone and estradiol. The aromatase activity in MCF-7 cells, which catalysed the conversion of testosterone to estradiol, was inhibited by a novel non-steroidal aromatase inhibitor, YM5111, with the IC50 of 0.2 nM, indicating that its inhibitory activity was 5.5 times more potent than that of CGS 16949A. YM511 inhibited the proliferation of MCF-7 stimulated by testosterone but did not inhibit the cell proliferation stimulated by estradiol. The IC50 values of YM511 for cell growth and DNA synthesis were 0.13 nM and 0.18 nM, respectively, demonstrating that YM511 was about 3-5 times more potent than CGS 16949A and had no anti-estrogenic or cytotoxic activity. YM511 significantly inhibited testosterone-stimulated transcriptional activation of estrogen-responsive element (ERE) in MCF-7 cells transfected transiently with ERE-luciferase reporter plasmid. The IC50 of YM511 for transactivation was 0.36 nM, suggesting that its inhibitory potency was comparable to the inhibition of aromatase activity of MCF-7 cells. These data may indicate that the inhibition by YM511 of cell proliferation of MCF-7 is attributed to the decreased production of estrogen due to the inhibition of aromatase activity. YM511 may be useful in the treatment of estrogen-dependent cancers.
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PMID:Inhibitory effect of a novel non-steroidal aromatase inhibitor, YM511 on the proliferation of MCF-7 human breast cancer cell. 880

Oestradiol (E2) is one of the most important factors supporting the growth and evolution of breast cancer; consequently, to block this hormone has been one of the main targets in recent years. The evaluation of oestrogens (oestrone, oestradiol and their sulphates) in the breast tissue of post-menopausal patients with breast cancer indicates high levels, particularly of oestrone sulphate (E1S) which is 15-25 times higher than in the plasma. Two main pathways are involved in the formation of oestrogens the sulphatase pathway which transforms E1,S into oestrone (E1), and the aromatase pathway which converts androgens into oestrogens. Comparative studies in breast cancer tissues show that the sulphatase pathway is 50-300 times more important than that of the aromatase pathway. Using intact cells and physiological concentrations of E1S (5 x 10(9)M) the conversion to oestradiol was very intense with the hormone-dependent (T-171). MCF-7) breast cancer cells, but very little or no E2 was obtained with the hormone-independent (MDA-MB-231, MDA-MB-436) cells. However, when the latter cells were homogenized, the oestrone sulphatase became very intense. This contradiction in the comparison of the sulphatase activity of the intact cell and the homogenate of the hormone-independent cells can be explained by the presence of inhibitory factors or the absence of positive factor(s) involved in the enzyme activity, which could be related to the evolution of the cancer to hormone-independence. Testing different substances, it was proven that promegestone (R-5020), and danazol, as well as decapeptyl in the presence of heparin, are very active in inhibiting sulphatase activity in hormone-dependent breast cancer cells. Using reverse transcriptase-PCR it was possible to detect the presence of oestrone sulphatase mRNA in different mammary cancer cells. The expression of this mRNA is significantly higher in T-471) and MDA-MB-231 than in the other cell lines. A correlation of this mRNA with the enzymatic activities of oestrone sulphate was observed. The progestagen, R-5020, can significantly decrease the sulphatase mRNA in MCF-7 and T-471) cells. As this progestagen can also inhibit the enzyme itself, it is suggested that the decrease in sulphatase activity by antisulphatase agents in breast cancer cells is a complex mechanism involving not only the effect on the enzyme but also the transcriptional factor(s). It is concluded that in addition to the control of aromatase, specific inhibition of oestrone sulphatase with antisulphatase agents can open new possibilities in breast cancer treatment.
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PMID:Control and expression of oestrone sulphatase activities in human breast cancer. 894 93

The expression of aromatase in human breast tumors has been studied by the reverse-transcription polymerase chain reaction (RT-PCR) method on 70 breast tissue specimens. An RT-PCR analysis using two oligonucleotide primers derived from the exon II of the human aromatase gene revealed that aromatase mRNA was detected in all but three tissue specimens. Furthermore, primer-directed RT-PCR was performed to determine the exon I usage in aromatase mRNA in these breast tumor specimens. The analysis has revealed that exons I.3 and PII are the two major exon Is present in aromatase mRNA isolated from breast tumors, suggesting that promoters I.3 and II are the major promoters driving aromatase expression in breast cancer and surrounding adipose stromal cells. The RT-PCR analysis also detected two products, I.3A (334 bp in length) and I.3B (222 bp in length), when it was carried out using a primer derived from exon I.3 and a reverse primer derived from exon II. The nucleotide sequences of these products have been determined and indicate that I.3A contains a region which was previously thought to be an intron. In addition, RT-PCR analyses of RNA isolated from eight pairs of breast tumor and neighboring normal tissue specimens were performed to evaluate the exon I usage and the distribution of I.3A- and I.3B-containing aromatase RNA messages in breast tumor and neighboring normal tissues. The results suggest that I.3B- and I.3A-containing messages are mainly present in breast tumor and neighboring normal tissues, respectively. Finally, the exon I/promoter usage for aromatase expression in eight cell lines (skin fibroblast, MCF-7, MDA-MB-231, T-47D, SK-BR-3, JAR, OVCAR-3, and human adipose stromal cells) was examined by primer-directed RT-PCR analyses. These studies provide a basis for further evaluation of the control mechanism of aromatase expression and estrogen biosynthesis in breast tumors.
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PMID:Aromatase gene expression and its exon I usage in human breast tumors. Detection of aromatase messenger RNA by reverse transcription-polymerase chain reaction. 901 Mar 31


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