Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1-[4-(2-Dimethylaminoethoxy)-phenyl]-1,2-diphenylbut-1-(Z)-ene (tamoxifen, TAM) is a nonsteroidal antiestrogen that has been commonly used for the prevention and treatment of estrogen receptor-positive breast cancer. TAM is extensively metabolized into several primary active metabolites including 4-hydroxy-TAM (4-OH-TAM) and endoxifen. Glucuronidation is the major phase II metabolic pathway important in their excretion. Whereas high antiestrogenic activity has been reported for both 4-OH-TAM and endoxifen, studies examining the effect of glucuronide conjugation of these metabolites have not previously been performed. In the present study, the antiestrogenic activities of glucuronidated TAM metabolites were determined by examining their effect on the induction of the estrogen-responsive progesterone receptor (PGR) gene. 17beta-Estradiol (E(2))-mediated PGR gene expression in MCF-7 cells was determined by real-time reverse transcriptase-polymerase chain reaction for each TAM metabolite isomer. E(2) (1 x 10(-10) M) induction of PGR mRNA was 6-fold after a 12-h incubation; only unconjugated TAM metabolites inhibited this effect. A virtually identical dose-dependent inhibition of E(2)-induced PGR gene expression was found for both the trans- and cis-isomers of 4-OH-TAM and endoxifen, with maximal inhibition attained at 1 x 10(-6) M of TAM metabolite. The glucuronide conjugates of all 4-OH-TAM and endoxifen isomers exhibited no effect on E(2)-mediated induction of PGR expression at all concentrations of TAM metabolite examined in this study. These data indicate that isomers of both 4-OH-TAM and endoxifen exhibit roughly equipotent antiestrogenic effects on E(2)-induced gene expression and that glucuronide conjugates of the same metabolites effectively negate this activity. This result may have important implications in terms of both whole-body and target tissue-specific glucuronidation pathways and individual responses to TAM therapy and cancer prevention.
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PMID:Elimination of antiestrogenic effects of active tamoxifen metabolites by glucuronidation. 1762 Mar 45

We previously showed that checkpoint kinase 1 (Chk1) and Claspin, two DNA-damage checkpoint proteins, were down-regulated by 1,25-dihydroxyvitamin D(3), a known inhibitor of cell proliferation. In the present study, we aimed to investigate the transcriptional regulation of Chk1 and Claspin and to study their expression levels in human breast cancer tissue. Transient transfection experiments in MCF-7 breast cancer cells showed that promoter activities of Chk1 and Claspin were regulated by the E2F family of transcription factors. Subsequently, transcript levels of Chk1, Claspin, and E2F1 were determined by quantitative reverse transcriptase-PCR analysis in 103 primary invasive breast carcinomas and were compared with several clinicopathologic variables in breast cancer. A strong correlation was found between Chk1 and Claspin transcript levels. Transcript levels of Chk1, Claspin, and E2F1 were highest in histologic grade 3 tumors and in tumors in which the expression of estrogen receptor (ER) and progesterone receptor (PR) was lost. Moreover, Chk1 expression was significantly elevated in grade 3 breast carcinomas showing a triple-negative ER-/PR-/HER-2- phenotype compared with other grade 3 tumors. Further research is warranted to validate the use of Chk1 inhibitors in triple-negative breast carcinomas for which treatment strategies are limited at present.
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PMID:The E2F-regulated gene Chk1 is highly expressed in triple-negative estrogen receptor /progesterone receptor /HER-2 breast carcinomas. 1763 66

Mixed epithelial stromal tumor of the kidney (MEST)/adult cystic nephroma (CN) is a lesion characterized by epithelial lined tubular or cystic structures interspersed within a variably prominent, distinctive spindle-cell stroma. Although typically benign, cases with malignant features have been reported. Herein, we report a MEST/CN with malignant stromal features and rhabdoid differentiation arising in the left kidney of an 84-year-old woman. Histologically, the tumor displayed multiple tubules and variably sized cystic structures lined by benign epithelium with an intervening malignant-appearing spindle-cell stroma. The malignant stroma displayed condensation in the regions surrounding the epithelial component consistent with the ovarian-like stroma typically observed in MEST/CN. In addition, the stromal cells displayed extensive rhabdoid differentiation. Immunohistochemical analysis revealed strong expression of cytokeratin 7, CAM 5.2, AE1/AE3, wide-spectrum keratin, and epithelial membrane antigen by the epithelial component. The stromal component displayed strong immunohistochemical expression of WT-1, CD-99, CD-56, INI1, and estrogen receptor; focal actin positivity; and was negative for desmin, myogenin, and progesterone receptor. Analysis by reverse transcriptase polymerase chain reaction failed to identify the SYT-SSX1 or SYT-SSX2 fusion transcripts characteristic of synovial sarcoma. To our knowledge, this represents the first report in the literature of malignant MEST with rhabdoid features and suggests that this entity should be considered in the diagnosis of renal stromal malignancies with prominent rhabdoid features.
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PMID:Malignant mixed epithelial and stromal tumor of the kidney with rhabdoid features: report of a case including immunohistochemical, molecular genetic studies and comparison to morphologically similar renal tumors. 1770 62

Mutations in the BRCA1-interacting DEAH helicase Brip1 confer an increased risk of breast cancer. In the present study we aimed to unravel the transcriptional control of Brip1 and to determine its expression levels in a set of 101 primary invasive breast carcinomas. Transcription of Brip1 was found to be cell growth-related and controlled by the E2F/retinoblastoma (Rb) pathway through a conserved E2F-responsive site. Repression of Brip1 expression by the cell growth-inhibiting compound 1alpha,25-dihydroxyvitamin D3 depended on this same E2F-responsive site. In spite of its role as a tumor suppressor, both quantitative reverse transcriptase-PCR analyses and immunohistochemical stainings showed significantly elevated Brip1 expression levels in grade 3 tumors as compared to grade 1 or 2 carcinomas. Furthermore, increased Brip1 transcript levels were found in tumors with an estrogen receptor-negative, progesterone receptor-negative or HER-2-positive status. In conclusion, these data show that Brip1 is a genuine target gene for the E2F/Rb pathway and that elevated expression levels of Brip1 are detected in primary invasive breast carcinomas with unfavorable characteristics.
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PMID:Expression of the BRCA1-interacting protein Brip1/BACH1/FANCJ is driven by E2F and correlates with human breast cancer malignancy. 1834 34

Oncotype DX is a commercially available reverse transcriptase-polymerase chain reaction based assay that provides a Recurrence Score (RS) and has been shown to provide prognostic and predictive information in estrogen receptor-positive lymph node-negative breast cancers. Independent studies of its utility in routine practice are lacking. Slides and surgical pathology reports from 42 cases of breast carcinomas evaluated by Oncotype DX were retrospectively reviewed to determine patient age, tumor size, histologic grade, estrogen and progesterone receptor (ER and PR) and ERBB2 (HER-2/neu) data, with ER and PR reported as a semi-quantitative score reflecting both intensity of staining and proportion of positive cells. We show here that Recurrence Score is significantly correlated with tubule formation, nuclear grade, mitotic count, ER immunohistochemical score, PR immunohistochemical score, and HER-2/neu status, and that the equation RS=13.424+5.420 (nuclear grade) +5.538 (mitotic count) -0.045 (ER immunohistochemical score) -0.030 (PR immunohistochemical score) +9.486 (HER-2/neu) predicts the Recurrence Score with an R2 of 0.66, indicating that the full model accounts for 66% of the data variability. Although the Oncotype DX Recurrence Score holds potential, further validation of its independent value beyond that of histopathologic analysis is necessary before it can be implemented in clinical decision making.
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PMID:Histopathologic variables predict Oncotype DX recurrence score. 1836 Mar 52

Although it is well established that some protein tyrosine kinases have a prognostic value in breast cancer, the involvement of protein tyrosine phosphatases (PTPs) is poorly substantiated for breast tumors. Three of these enzymes (PTP-gamma, LAR, and PTPL1) are already known to be regulated by estrogens or their antagonists in human breast cancer cells. We used a real-time reverse transcriptase polymerase chain reaction method to test the expression levels of PTP-gamma, LAR and its neuronal isoform, and PTPL1 in a training set of RNA from 59 breast tumors. We sought correlations between levels of these molecular markers, current tumor markers, and survival. We then quantified the expression level of the selected phosphatase in 232 additional samples, resulting in a testing set of 291 breast tumor RNAs from patients with a median follow-up of 6.4 years. The Spearman nonparametric test revealed correlations between PTPL1 expression and differentiation markers. Cox univariate analysis of the overall survival studies demonstrated that PTPL1 is a prognostic factor [risk ratio (RR)=0.45], together with the progesterone receptor (PR) (RR=0.52) and node involvement (RR=1.58). In multivariate analyses, PTPL1 and PR retained their prognostic value (RRs of 0.48 and 0.55, respectively). This study demonstrates for the first time that PTPL1 expression level is an independent prognostic indicator of favorable outcome for patients with breast cancer. In conjunction with our mechanistic studies, this finding identifies PTPL1 as an important regulatory element of human breast tumor aggressiveness and sensitivity to treatments such as antiestrogens and antiaromatase.
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PMID:Expression of the putative tumor suppressor gene PTPN13/PTPL1 is an independent prognostic marker for overall survival in breast cancer. 1900 8

To explore how progesterone affects human pregnancy, we identified the progesterone target cells within the fetal membranes (amnion, chorion, and decidua) at term by assessing the extent of expression and localization of the nuclear progesterone receptors, progesterone receptor-A and progesterone receptor-B. Fetal membranes (separated into amnion and chorion-decidua) were obtained after term cesarean deliveries performed before (n = 7) and after (n = 7) labor onset. Nuclear progesterone receptor expression was determined by the abundance of nuclear progesterone receptor mRNAs (by quantitative reverse transcriptase-polymerase chain reaction) and proteins (by western blotting). Localization of nPRs was determined by immunohistochemistry. Progesterone receptor-A and progesterone receptor-B mRNA and protein levels were highest in the chorion-decidua and did not change in association with labor. Nuclear progesterone receptor mRNAs and proteins were barely detectable in amnion. Nuclear progesterone receptor immunostaining was detected only in the nucleus of decidual cells. These findings suggest that the decidua, and not the amnion and chorion, is a direct target for nuclear progesterone receptor-mediated progesterone actions during human pregnancy.
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PMID:Nuclear progesterone receptor expression in the human fetal membranes and decidua at term before and after labor. 1919 77

The purpose of the present study is to identify genes that contribute to cell proliferation or differentiation of breast cancers independent of signalling through the oestrogen receptor (ER) or human epidermal growth factor receptor 2 (HER2). An oligonucleotide microarray assayed 40 tumour samples from ER(+)/HER2(-), ER(+)/HER2(+), ER(-)/HER2(+), and ER(-)/HER2(-) breast cancer tissues. Quantitative reverse transcriptase PCR detected overexpression of a cell cycle-related transcription factor, E2F-5, in ER-negative breast cancers, and fluorescence in situ hybridisation detected gene amplification of E2F-5 in 5 out of 57 (8.8%) breast cancer samples. No point mutations were found in the DNA-binding or DNA-dimerisation domain of E2F-5. Immunohistochemically, E2F-5-positive cancers correlated with a higher Ki-67 labelling index (59.5%, P=0.001) and higher histological grades (P=0.049). E2F-5-positive cancers were found more frequently in ER(-)/progesterone receptor (PgR)(-)/HER2(-) cancer samples (51.9%, P=0.0049) and in breast cancer samples exhibiting a basal phenotype (56.0%, P=0.0012). Disease-free survival in node-negative patients with E2F-5-positive cancers was shorter than for patients with E2F-5-negative cancers. In conclusion, we identify, for the first time, a population of breast cancer cells that overexpress the cell cycle-related transcription factor, E2F-5. This E2F-5-positive breast cancer subtype was associated with an ER(-)/PgR(-)/HER2(-) status, a basal phenotype, and a worse clinical outcome.
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PMID:Overexpression of E2F-5 correlates with a pathological basal phenotype and a worse clinical outcome. 1925 95

Fifty-one meningiomas obtained from 28 dogs and 23 cats were selected for this study to investigate the immunohistochemical expression of matrix metalloproteinase (MMP)-2 and MMP-9 and to compare it to the reverse transcriptase subunit of human-telomerase, progesterone receptor expression, and the proliferative index of the tumors, expressed by Ki67 and proliferating cellular nuclear antigen. Paraffin-embedded tumor tissue was obtained from biopsy samples (28 cases) and at necropsy (23 cases). The most common histotype was malignant in dogs (12/28) and transitional in cats (12/23). Slides immunolabelled for MMPs showed a diffuse cytoplasmic pattern. Twenty-one cases (19 dogs and 2 cats) did not express MMP-2, while only 2 cases were completely negative for MMP-9. The highest values of MMP-2 and MMP-9 were observed in a psammomatous and meningothelial tumor, respectively. On statistical analysis, MMP-2 expression did not show a significant correlation with MMP-9. Moreover, both MMP expressions failed to show significant variance among histologic patterns of the tumor and correlation with the proliferative index. MMP immunolabeling showed an inconstant correlation with progesterone receptor expression. No significant correlation was found between MMP and reverse transcriptase subunit of human-telomerase expression. In feline meningiomas, the MMP-2 value was significantly higher than in canine tumors and the MMP-9 value tended to be low for meningiomas with a follow-up duration from the 23(rd) month to the 44(th) month. In cats, the longer the time from surgery, the lower the proliferative index seemed to be. In dogs, we failed to find a correlation between MMP expression and the follow-up duration.
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PMID:Matrix metalloproteinase-2 and matrix metalloproteinase-9 expression in canine and feline meningioma. 1927 56

Micro-RNAs are a group of small noncoding RNAs approximately 22 nucleotides in length. Recent work has shown differential expression of mature micro-RNAs in human cancers. We characterized the alteration in expression of miR-29b in ovarian serous carcinoma. miR-29b expression was analyzed using quantitative stem-loop reverse transcriptase polymerase chain reaction on a set of 50 formalin-fixed, paraffin-embedded ovarian serous carcinoma samples. Protein expression of p53, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki-67, and insulinlike growth factor 1 was quantified in the corresponding tissue microarray. The expression profile of miR-29b was correlated with clinicopathological and patient survival data. We provide definitive evidence that miR-29b is down-regulated in a significant proportion of ovarian serous carcinomas and is associated with specific clinicopathological features, most notably high miR-29b expression being associated with reduced disease-free survival.
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PMID:miR-29b expression is associated with disease-free survival in patients with ovarian serous carcinoma. 1950 63


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