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)

Specific activity of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) was measured in 48 tissue specimens of human female breast cancer and, in addition, 48 nonmalignant tissue specimens obtained in each case from the same cancer-bearing breast. In all cases the nonmalignant tissue showed greater conversion of estradiol-17 beta into estrone than the neoplastic tissues. In normal human breast tissue of premenopausal women specific enzyme activity depended on the phase of the MENSTRUAL CYCLE: the highest values of 17 beta-HSD activity were found in the early secretory phase. To determine the intracellular distribution of the 17 beta-HSD, purified microsomes, mitochondria, peroxysomes, lysosomes, nuclei and cytosol fractions were prepared. The purity of each fraction was monitored by marker enzymes. It was found that the 17 beta-HSD was mainly located in mitochondria and microsomes. Furthermore it could be demonstrated that the microsomal enzyme was bound tightly to the membranes of the endoplasmic reticulum, while the mitochondrial 17 beta-HSD was mainly associated with the outer membranes of the organelle. Kinetic parameters (Km-values, coenzyme requirements and maximal velocities) of a cytoplasmic, nuclear, mitochondrial and microsomal 17 beta-HSD of normal and neoplastic human mammary tissue were compared. Maximal velocity was highest in enzyme preparations of normal mammary tissue obtained from premenopausal women in the early secretory phase. Km-values wrere nearly identical in normal and neoplastic mammary tissue preparations (approx. 1 X 10(-6) M). NAD was more efficient than NADP as a cofactor. For the conversion of estradiol to estrone the optimum temperature was approximately 40 degrees C and the optimum pH 9.5. For the reduction of estrone the optimum pH was 6.5. Sulphydryl groups were shown to be essential for catalysis.
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PMID:Comparison of the in vitro conversion of estradiol-17 beta to estrone of normal and neoplastic human breast tissue. 1 41

MCF-7 human breast cancer cells propagated in vitro were treated with adenosine derivatives added to the culture medium. The effects on cell proliferation, glycolysis, and glutaminolysis were investigated. Of all adenosine derivatives tested, AMP was the most efficient inhibitor of cell proliferation. In AMP-treated cells, DNA synthesis decreased, whereas RNA and protein syntheses rose normally with time. In terms of carbohydrate metabolism, lactate production from glucose was drastically reduced; therefore, most of lactate produced must have been derived from glutamine. Increases in the enzyme activities involved in glutamate degradation and in the malate-aspartate shuttle were observed. In contrast, actual glycolytic flux rates declined, whereas key glycolytic enzyme activities increased. Metabolites such as fructose 1,6-bisphosphate and pyruvate accumulated in AMP-arrested cells. Based on the lowered NAD level in the AMP-treated cells, lactate dehydrogenase, but not malate dehydrogenase, was impaired; thereby the whole of glycolysis was inhibited. In compensation, glutamine catabolism was increased. NAD concentrations fell drastically because of the known inhibition of P-ribose-PP synthesis through heightened intracellular AMP levels. A hypothetical metabolic scheme to explain these results and to show how extracellular AMP may influence carbohydrate metabolism and cell proliferation is presented.
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PMID:In vitro effect of extracellular AMP on MCF-7 breast cancer cells: inhibition of glycolysis and cell proliferation. 144 15

Activity of NAD-dependent 17 beta-hydroxysteroid dehydrogenase (E2DH), the enzyme which converts estradiol (E2) into its less active metabolite estrone (E1), has been previously characterized in normal human breast cells in culture and in benign and malignant breast tumors. E2DH activity is far greater in epithelial cells than in fibroblasts. Moreover, it is progesterone dependent in epithelial cells. It was therefore interesting to explore E2DH in the progesterone receptor (PR)-rich T47D cell line as a possible marker of hormone dependence in breast cancer cells. In T47D cells, transformation of [3H]E2 to E1 is limited. The metabolism seems to be preferentially oriented in the way E1----E2 in these cells. However, in the presence of the cofactor NAD the conversion of E2 into E1 increases. Moreover, treatment of T47D cells in culture by the progestin R5020 stimulates E2 to E1 conversion 2- to 3-fold. Stimulation of E2DH (E2----E1) activity reflects both the presence and the operability of PR. This observation underlines the possible interest of E2DH assay in parallel to estradiol receptor and PR to evaluate hormone-dependence of breast cancer.
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PMID:17 beta-estradiol dehydrogenase (E2DH) activity in T47D cells. 195 11

The identification of several steroid-transforming enzymes within human breast cancers has led to speculation that the growth of some hormone-responsive tumors might be mediated in part by intracellularly derived estrogens. Reports that MCF-7 human breast cancer cells can transform both estrone (E1)1 to estradiol (E2) and dehydroepiandrosterone (DHEA) to the estrogenic steroid 5-androstenediol (AED), have prompted us to investigate the 17-ketosteroid reductase activities (17-KSR's) which mediate these potentially important reactions. Enzyme assays were performed by quantifying the amounts of [3H]AED or [3H]E2 former from [3H]DHEA or [3H]E1, respectively, by various subcellular preparations from MCF-7 cells under a variety of experimental conditions. DHEA 17-KSR was found to be localized exclusively within cytosol, whereas the E1 17-KSR activity appeared to be nearly equally divided between the soluble and particulate cytoplasmic subfractions. The particulate E1 17-KSR appeared capable of utilizing NADH or NADPH, whereas both the cytosolic form of this enzyme and the soluble DHEA 17-KSR activity showed a strict requirement for NADPH. Although both of the soluble 17-KSR's also showed similar pH optima, several other features suggested that they are different enzymes in MCF-7. E1 did not inhibit the conversion of DHEA to AED, and DHEA did not interfere with the transformation of E1 to E2, indicating that major differences in substrate specificity exist between the two cytosolic activities. Furthermore, DHEA 17-KSR activity within cytosol stored at -20 degrees C deteriorated almost completely over twelve weeks of storage, whereas E1 17-KSR activity remained stable. Finally, although both enzymes were found to be subject to product inhibition, AED inhibited DHEA 17-KSR competitively, whereas cytosolic E1 17-KSR activity was inhibited by E2 in noncompetitive fashion. Studies of the oxidation of E2 to E1 by MCF-7 cells showed that this transformation is catalyzed by both soluble and particulate 17-hydroxysteroid oxidases which utilize either NAD or NADP as cofactor. Having previously reported the presence of a particulate NADP(H)-linked androstenedione (AE) 17-ketosteroid oxidoreductase in MCF-7, we now suggest that at least three different enzymes, one particulate and two soluble forms, participate in the conversion of 17-ketosteroids to their hormonally active 17-hydroxysteroid derivatives within this cell line. The restricted substrate requirements of each enzyme provide a rationale for developing selective enzyme inhibitors which could provide important investigational tools and potentially effective therapeutic agents.
Breast Cancer Res Treat 1990 Oct
PMID:Dehydroepiandrosterone and estrone 17-ketosteroid reductases in MCF-7 human breast cancer cells. 196 14

The activity of the oestradiol-17 beta hydroxysteroid dehydrogenase in human endometrial and breast cancer specimens was determined by the NAD-dependent conversion of oestradiol-17 beta to oestrone. The sensitivity of the determination was improved by the separation of the hormones by HPLC. We are now able to determine oestradiol-17 beta hydroxysteroid dehydrogenase quantitatively in cryostat sections. A clear correlation of serum progesterone levels and oestradiol-17 beta hydroxysteroid dehydrogenase activity in the endometrium was demonstrated, and we found a more than 30-fold increase in enzyme activity after the progesterone surge. In contrast, in breast cancer samples, we found no correlation between oestradiol-17 beta hydroxysteroid dehydrogenase and the measured serum parameters.
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PMID:Quantitative determination of oestradiol-17 beta hydroxysteroid dehydrogenase: increased sensitivity by HPLC separation of the hormones permits the measurement of enzyme activity in cryostat sections. 322 Nov 76

The kinetic properties of oestradiol 17 beta-dehydrogenase have been studied in the MCF-7 human breast cancer cell line. The activity of the enzyme was found to be linear with respect to time for at least 2 h and with respect to protein concentrations over the range 40-300 micrograms protein per tube. The enzyme was able to utilize both NAD and NADP as cofactors but at higher concentrations NAD was the more effective. The apparent Km was estimated to be 13.4 microM which is approximately two-fold higher than found for breast tumour tissue.
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PMID:Kinetic studies of oestradiol 17 beta-hydroxysteroid dehydrogenase in MCF-7 mammary cancer cells. 386 10

Plasma levels of total tryptophan were significantly lower in 51 patients with breast cancer than in 14 women with benign breast cancer following surgery and after 12 weeks. The urinary excretion of xanthurenic and 5-hydroxyindoleacetic acids were similar in patients with cancer and benign disease but the excretion of N'-methylnicotinamide (NMN) was significantly higher (P less than 0.001) in the cancer patients. It is suggested that the elevated urinary excretions of NMN is due to higher NAD activity reflecting elevated glycolysis through the Cori cycle.
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PMID:Tryptophan metabolism in patients with breast cancer. 403 62

Mitomycin C (MMC) is a bioreductive antitumor agent that is activated by NADPH:cytochrome P450 reductase (EC 1.6.2.4) and NAD(P)H:(quinone acceptor) oxidoreductase (EC 1.6.99.2) (DT-diaphorase). DT-diaphorase is a two-electron reducing enzyme that is induced by a variety of chemicals, including quinones. Doxorubicin (DOX) is an anthraquinone antitumor agent that has been used clinically with MMC for combination chemotherapy in breast cancer. In this study, we investigated whether DOX could selectively induce DT-diaphorase in tumor cells and whether combining this agent with MMC in an appropriate schedule could produce synergistic antitumor activity. Treatment of EMT6 murine mammary tumor cells with DOX resulted in a 40% increase in DT-diaphorase activity in these cells, but had no effect on this enzyme in murine bone marrow cells. Combination therapy with DOX and MMC produced a 1.4-fold level of synergistic cell kill in the tumor cells, but a similar level of synergy was also observed in normal bone marrow cells. Thus, DOX can selectively induce elevated levels of DT-diaphorase in tumor cells; however, the synergy observed by combining this agent with MMC appears to be unrelated to the induction of DT-diaphorase.
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PMID:Induction of DT-diaphorase by doxorubicin and combination therapy with mitomycin C in vitro. 748 45

We have used 31P- and 13C-nuclear magnetic resonance spectroscopy to measure key metabolite levels and fluxes through enzymes regulating phospholipid and mitochondrial metabolism in normal human mammary epithelial cells. We have compared these values to those found in a progression series of breast cancer cell lines of varying metastatic potential established from a single patient. We find a 16-19-fold increase in phosphocholine content in two primary breast cancer cell lines (21PT and 21NT) and a 27-fold increase in phosphocholine content in the metastatic breast cancer cell line (21MT-2) compared with the normal breast epithelial cell strain 76N. Thus, phosphocholine may serve as a metabolic marker for the human breast cell progression state. A 30% decrease in ATP levels, a 83% decrease in phosphocreatine levels, along with a 2-fold increase in NAD(+) + NADH levels in 21PT, 21NT, and 21MT-2 cells compared to the normal breast cells further suggests impaired mitochondrial metabolism in the breast carcinoma cell lines. Consistent with this suggestion is our finding that the primary breast cancer cell lines (21PT and 21NT) and the metastatic breast cell line (21MT-2) showed a 50 and 89% relative reduction, respectively, in the flux of pyruvate utilized for mitochondrial energy generation compared to pyruvate utilized to replenish tricarboxylic acid cycle intermediates. These results demonstrate that diminished mitochondrial energy generation may be quantitatively related to the progression state of human breast cells.
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PMID:Pyruvate utilization, phosphocholine and adenosine triphosphate (ATP) are markers of human breast tumor progression: a 31P- and 13C-nuclear magnetic resonance (NMR) spectroscopy study. 758 61

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds elicit diverse toxic and biochemical responses in laboratory animals and mammalian cells in culture. TCDD induces CYP1A1 gene expression and results of extensive research have delineated the molecular mechanism of this response. In target cells, TCDD initially binds to the aryl hydrocarbon (Ah) receptor which accumulates in the nucleus as an Ah-receptor:aryl hydrocarbon nuclear translocator (Arnt) protein heterodimeric complex. The nuclear Ah receptor complex acts as a ligand-induced transcription factor which binds to transacting genomic dioxin/xenobiotic responsive elements (DREs/XREs) located in the 5'-regulatory region upstream from the initiation start site and this interaction results in transactivation of gene transcription. DREs have been identified in several other genes which are induced by TCDD, including CYP1A2, aldehyde-3-dehydrogenase, NAD(P)H quinone oxidoreductase, and glutathione S transferase Ya and similar induction response pathways have been observed or proposed. However, TCDD and other Ah receptor agonists also inhibit expression of several genes and research in this laboratory has investigated inhibition of estrogen (E2)-induced genes including uterine epidermal growth factor, c-fos protooncogene, and the progesterone receptor, estrogen receptor (ER) and cathepsin D genes in human breast cancer cell lines. In MCF-7 human breast cancer cells, E2 induces cathepsin D gene expression and this is associated with formation of an ER/Sp1 complex at the sequence in the promoter region (-199/-165) of this gene. Within 30 min TCDD causes a rapid inhibition of E2-induced cathepsin D gene expression in MCF-7 cells. Moreover, using a series of synthetic oligonucleotides which include the wild-type ER/Sp1 and various mutants, it was shown by gel electromobility shift and transient transfection assays that the nuclear Ah receptor complex binds to an imperfect DRE located between the ER and Sp1 binding sequences. This interaction results in disruption of the ER/Sp1 complex and inhibition of E2-induced gene expression. These results illustrate that the nuclear Ah receptor complex also exhibits activity as a negative transcription factor via a mechanism which is similar to that reported for Ah receptor-mediated induction of gene expression.
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PMID:Cellular and molecular biology of aryl hydrocarbon (Ah) receptor-mediated gene expression. 778 96


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