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Query: UNIPROT:P06889 (Mol)
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The factor(s) which regulate the rapid growth of ovarian epithelial carcinoma, as well as other types of malignant tumors, are still largely unknown. Recently, experimental evidence indicated that neoplastic cells are able to synthesize peptide growth factor and their receptors. This autocrine secretion could be one of the mechanisms to sustain their abnormal proliferation. In this study, we evaluated the possible role of basic fibroblast growth factor (bFGF) that is a likely candidate because it has both angiogenic and mitogenic activity and has been found in a variety of other neoplasms. As assessed by both bioassay and radioimmunoassay, a bFGF-like protein was present in seven ovarian epithelial neoplasms and in primary culture of dispersed ovarian cancer cells. Levels of this protein as well as its bioactivity varied in the different tumors examined. Reverse transcription-polymerase chain reaction indicated that the genes for bFGF and its receptor are expressed in all the samples studied. These data suggest that bFGF might be one of the growth factor regulating ovarian cancer cell proliferation through an autocrine mechanism. We are currently investigating whether the expression of this growth factor varies as a function of the histologic grade of the tumors.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Basic fibroblast growth factor and ovarian cancer. 762 84

The expression of the c-fos proto-oncogene was studied in two sublines of the human ovarian cancer cell line SW626. One subline (SW/B) presents the typical 2.0 kb mRNA which is detectable within 15 min. after serum stimulation of quiescent cells, is inducible by protein synthesis inhibitors and has a half-life of approximately 10-15 min. The other subline (SW/A) does not show the 2.0 kb mRNA, but instead presents a mRNA of higher molecular weight capable of hybridizing with the c-fos probe. This bigger mRNA is neither serum inducible nor sensitive to protein synthesis inhibitors. The presence of this transcript is not due to any gross alteration in the gene structure. Differences were found in the DNA binding proteins obtained from nuclei of the two sublines. A protein able to bind the promoter of c-fos was found in SW/B but not in SW/A. In the latter subline no amplification products were observed using two different sets of primers covering the 3' coding region of the human gene. Conversely, the expected fragments were amplified from mRNA obtained from the SW/B subline.
Cell Mol Biol (Noisy-le-grand) 1995 Mar
PMID:Differential expression of c-fos proto-oncogene in two subclones derived from a human ovarian cancer cell line. 778 35

A gene for hereditary breast and ovarian cancer, BRCA1, has been mapped to chromosome 17q12-q21. This gene is responsible for cancer susceptibility in the majority of families with multiple cases of ovarian cancer and early-onset breast cancer. We report linkage results of a family with 10 cases of breast cancer and a single case of ovarian cancer. A recombinant event in this family places BRCA1 distal (telomeric) to the locus EDH17B2, which codes for the enzyme estradiol 17 beta-dehydrogenase II. This recombinant is based on the appearance of breast cancer in a 45 year old woman. Under our genetic model, we estimate the probability that this woman carries a BRCA1 mutation to be 94%. These data further reduce the region of assignment of BRCA1 on chromosome 17q12-q21 and should expedite positional cloning of this important gene.
Hum Mol Genet 1994 Sep
PMID:The gene for hereditary breast-ovarian cancer, BRCA1, maps distal to EDH17B2 in chromosome region 17q12-q21. 783 28

NIH:OVCAR-3 is a human ovarian cancer cell line that expresses a moderate amount of estrogen receptors, 28 fmol/mg protein. We have found that estrogen at a concentration of 10(-7) M induced a 2.3-fold increase in the growth of NIH:OVCAR-3 cells after 48 h stimulation. A 4-fold increase in c-myc mRNA expression at 30 min and a 7.5-fold increase at 50 min post-induction with estradiol were observed. Nuclear run-on analysis indicated that c-myc transcripts increased 4-fold within 10 min of estrogen addition. The half-life of c-myc mRNA was 64 min +/- 5 min and was not affected by estrogen. Antisense oligonucleotide to c-myc specifically inhibited the estrogen stimulated c-myc protein expression as well as the growth of NIH:OVCAR-3 cells. A control ovarian cancer cell line OC-3-VGH that had few estrogen receptors (1 fmol/mg protein) did not respond to estrogen in growth; however, these cells respond to estrogen with a 1.5-fold increase in c-myc mRNA. The stability of c-myc mRNA of these cells was not affected by estrogen. Our results indicate that transcriptional induction of c-myc expression by estrogen plays a critical role in the proliferation of NIH:OVCAR-3 cells.
Mol Cell Endocrinol 1994 Feb
PMID:Transcriptional activation of c-myc proto-oncogene by estrogen in human ovarian cancer cells. 818 52

We have analyzed a single multi-affected breast/ovarian cancer pedigree (BOV3) and have shown consistent inheritance of markers on chromosome 17q with the disease confirming that this family is due to the BRCA1 gene. Analysis of 17q haplotypes shows a recombination event in a bilateral breast cancer case which suggests that the BRCA1 gene lies distal to D17S857; D17S857 is thus the new proximal boundary for the region containing BRCA1. Combining this information with previously published mapping information suggests that BRCA1 is contained in a region estimated at 1-1.5 Mb in length. All seven breast tumour/blood pairs examined from this family show loss of heterozygosity in the tumours. The allel retained in each tumour was from the disease-bearing chromosome implicating BRCA1 as a tumour suppressor gene. We have sequenced the 17 beta-oestradiol dehydrogenase genes (EDH17B1 and EDH17B2) which have been suggested as candidate genes for BRCA1 in four members of this family. No germline mutations were detected.
Hum Mol Genet 1993 Nov
PMID:Genetic analysis of the BRCA1 region in a large breast/ovarian family: refinement of the minimal region containing BRCA1. 828 Nov 42

The human estradiol 17 beta-hydroxysteroid dehydrogenase II (17 beta-HSD II) gene has been assigned by somatic cell hybridization to chromosome 17q11-q21, near the region of assignment of the gene BRCA1, which is involved in hereditary breast-ovarian cancer. The nucleotide sequence of 17 beta-HSD II was completely determined in four unrelated individuals. Direct sequencing of PCR fragments that span the complete 17 beta-HSD II gene revealed a total of 11 allelic variants which were due to single base substitutions. The presence of these variants was then studied in twenty six additional unrelated individuals. There were nine frequent and two rare polymorphisms. Seven of the 11 polymorphisms were in complete linkage disequilibrium. These polymorphisms in the 17 beta-HSD II gene provide markers that can be used for the genetic mapping of this locus, and may be used to establish whether 17 beta-HSD II is a candidate gene for hereditary breast-ovarian cancer.
Hum Mol Genet 1993 Apr
PMID:Detection of polymorphisms in the estradiol 17 beta-hydroxysteroid dehydrogenase II gene at the EDH17B2 locus on 17q11-q21. 838 26

A susceptibility gene for hereditary breast-ovarian cancer, BRCA1, has been assigned by linkage analysis to chromosome 17q21. Candidate genes in this region include EDH17B2, which encodes estradiol 17 beta-hydroxysteroid dehydrogenase II (17 beta-HSD II), and RARA, the gene for retinoic acid receptor alpha. We have typed 22 breast and breast-ovarian cancer families with eight polymorphisms from the chromosome 17q12-21 region, including two in the EDH17B2 gene. Genetic recombination with the breast cancer trait excludes RARA from further consideration as a candidate gene for BRCA1. Both BRCA1 and EDH17B2 map to a 6 cM interval (between THRA1 and D17S579) and no recombination was observed between the two genes. However, direct sequencing of overlapping PCR products containing the entire EDH17B2 gene in four unrelated affected women did not uncover any sequence variation, other than previously described polymorphisms. Mutations in the EDH17B2 gene, therefore do not appear to be responsible for the hereditary breast-ovarian cancer syndrome. Single meiotic crossovers in affected women suggest that BRCA1 is flanked by the loci RARA and D17S78.
Hum Mol Genet 1993 Aug
PMID:Genetic mapping of the breast-ovarian cancer syndrome to a small interval on chromosome 17q12-21: exclusion of candidate genes EDH17B2 and RARA. 840 1

Aromatase activity, as well as steroid receptors, exists in nonfunctional ovarian tumors. Steroid receptor status has been reported to be related to prognosis in ovarian cancer patients. We determined aromatase activity and progesterone receptor (PR) and estrogen receptor (ER) levels in 43 ovarian tumors obtained from postmenopausal women. Aromatase activity was detected in 35 tumors (81%), PR in 21 tumors (49%) and ER in 13 tumors (30%). Eighty-three percent (10/12) of mucinous cystadenoma tissues showed positive PR with high aromatase activity, while 93% (13/14) of malignant tumors showed negative PR and low aromatase activity. Aromatase activity was detected in 95% (20/21) of PR-positive tumors, being greater than in PR-negative tumors (P < 0.002). There was a positive correlation between aromatase activity and PR (rs = 0.49, P < 0.001). However, there was no correlation between aromatase activity and ER. In 17 patients (43%), the serum estradiol level was higher than 30 pg/ml and there was a positive correlation among estradiol, estrone, androstenedione and testosterone. However, serum steroid levels were not correlated with aromatase activity, PR or ER. Aminoglutethimide inhibited aromatase activity of benign and malignant ovarian tumors, uterine myoma, choriocarcinoma cells and purified human placental P-450arom in a similar manner. These results suggest that aromatase activity is correlated with PR in ovarian tumors of postmenopausal women. In addition to steroid receptor status, aromatase activity may be a useful prognostic factor in ovarian cancers.
J Steroid Biochem Mol Biol 1993 Mar
PMID:Relationship between aromatase activity and steroid receptor levels in ovarian tumors from postmenopausal women. 847 78

Estrogen receptor positive ovarian cancer is often refractile to antiestrogen therapy. Here we describe the SKOV3 human ovarian carcinoma cell line as an in vitro model for estrogen and antiestrogen resistant ovarian cancer. While SKOV3 cells expressed estrogen receptor (ER) mRNA and protein at a similar level as the estrogen responsive T47D breast carcinoma cell line, their growth was not responsive to estradiol (E2) and was not inhibited by the antiestrogens OH-tamoxifen and ICI 164,384. The ER in SKOV3 cells was normal with respect to apparent Kd for binding with E2, E2 regulation of a transiently transfected ERE driven reporter gene, and E2 stimulation of expression of the early growth response genes c-myc and c-fos. However, the SKOV3 cells exhibited no expression of the progesterone receptor gene (PR) even after addition of E2, and the protein products of the estrogen responsive genes HER-2/neu and cathepsin D were expressed at constitutive levels that were not regulated by E2. Therefore, estrogen resistance in these cells may be a result of constitutive expression and loss of E2 regulation of selected growth regulatory gene products rather than a defect in estrogen activation of ER as a transcriptional regulator.
J Steroid Biochem Mol Biol 1995 Dec
PMID:SKOV3 ovarian carcinoma cells have functional estrogen receptor but are growth-resistant to estrogen and antiestrogens. 854 Dec 24

An estimated 5 to 10% of all breast and ovarian cancer is attributable to inherited mutations in two highly penetrant autosomal dominant susceptibility genes, BRCA1 and BRCA2. BRCA1 confers higher risk of ovarian cancer and BRCA2 much higher risk of male breast cancer. With the exception of missense mutations in the RING finger near the amino terminus of BRCA1, virtually all germline mutations in the gene cause the novel BRCA1 protein to be prematurely truncated. Approximately 90% of breast tumors in BRCA1 families, 50% of unselected breast tumors and 65-80% of unselected ovarian tumors have lost one allele of BRCA1 by somatic deletion. Very few tumors have detectable somatic point mutations in BRCA1. Inhibition of BRCA1 expression in mammary epithelial cell lines also suggests that BRCA1 may act as a tumor suppressor. The biological function of BRCA1 is still unknown, although identification of a patient homozygous for an inherited BRCA1 mutation suggests that the gene's function may be essential only to specific tissues. At least two other genes, P53 and the androgen receptor, are responsible for inherited predisposition to breast cancer in rare families. Several epidemiologic studies suggest that individuals carrying rare alleles at a minisatellite flanking the HRAS locus are at increased risk of cancer, including breast cancer. Finally, preliminary epidemiologic studies also suggest that individuals heterozygous for mutations in the ataxia telangiectasia gene may be at increased risk of breast cancer.
Hum Mol Genet 1995
PMID:Inherited breast and ovarian cancer. 854 81


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