Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q7LGC8 (HSD)
 3,196 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

The expression of the 17 beta-hydroxysteroid dehydrogenase (17-HSD) gene in a series of human breast cancer cell lines was studied by Northern blot hybridization with a cDNA probe and by a time-resolved immunofluorometric assay using polyclonal antibodies against the enzyme protein. The 17-HSD enzyme protein concentration was measured in the 800 x g cell extract. A high concentration was measured in the BT-20 cell line, corresponding to one-fourth of the average concentration in placental tissue. Western blot analysis indicated that the antigen corresponded to a single Mr 35,000 band. In 2 other cell lines (MDA-MB-361 and T-47D), the 17-HSD protein concentration was much lower, but still measurable, whereas in the remaining 5 cell lines (HBL-100, MCF-7, MDA-MB-231, MDA-MB-468, and ZR-75-1) it was below the detection limit of the assay. Treatment of the cells for 5 days with the synthetic progestin, ORG2058, resulted in an increase of the 17-HSD protein concentration only in the T-47D cell line. By Northern blot analysis, a low level of 2.3-kilobase mRNA transcripts was detected in all 8 cell lines. In addition, a 1.3-kilobase 17-HSD mRNA was present in the samples from the 3 cell lines containing measurable amounts of 17-HSD protein in the cell extract, and the band intensities were proportional to the amount of protein measured with the immunofluorometric assay. Only in the T-47D cell line did progestin treatment correspond to an increased amount of the 17-HSD 1.3-kilobase mRNA. These results suggest that the 1.3-kilobase mRNA for 17-HSD is the form most closely associated with protein expression and is also the only form responding to the progestin induction of the 17-HSD gene.
Cancer Res 1992 Jan 15
PMID:17 beta-hydroxysteroid dehydrogenase gene expression in human breast cancer cells: regulation of expression by a progestin. 172 3

The expression of 17 beta-hydroxysteroid dehydrogenase (17-HSD) enzyme protein was studied in benign and malignant human breast tissue using the time-resolved immunofluorometric assay (IFMA), immunoblotting and immunohistochemistry. The presence and distribution of estrogen and progestin receptors was also analyzed immunohistochemically. Cytosolic 17-HSD concentrations in malignant breast specimens were highly variable (less than or equal to 0.2-311 ng/mg protein). As was previously found for the placental enzyme, the molecular weight of the 17-HSD expressed in malignant breast tissue was 35 kDa, estimated following polyacrylamide gel electrophoresis and immunoblotting. The cellular distribution of 17-HSD was further studied by immunohistochemistry. Immunostaining for 17-HSD was observed in 71% of the benign breast lesions (fibroadenomas and cases of mastopathia chronica) and in 47% of the cancer specimens (intra-ductal carcinomas, invasive ductal carcinomas). In benign lesions, the staining was exclusively localized in the cytoplasm of epithelial cells, with no immunoreactivity in the stromal cells. The staining in the cancer specimens was also detected only in the cytoplasm of malignant epithelial cells. A strong or moderate expression of 17-HSD was related to the presence of PR in the specimen (chi 2 = 4.657, p = 0.031). However, the expression of PR was not a prerequisite for expression of 17-HSD in all the cancer specimens. Our data suggest that, in addition to the reported regulation of 17-HSD by progestins, other factors are also involved in this process in breast tissue.
Int J Cancer 1992 Feb 01
PMID:Immunological analysis of 17 beta-hydroxysteroid dehydrogenase in benign and malignant human breast tissue. 173 7

Steroid regulation of 17 beta-hydroxysteroid dehydrogenase (17-HSD) was studied in the T-47D human breast-cancer cell line, using a radioimmunoassay. In addition, 3 mRNA species (2.4, 1.4, and 0.9 kb) specific for the enzyme were shown to be present in these cells. All the synthetic progestins tested (ORG 2058, R5020, medroxyprogesterone acetate) significantly increased the immunoreactive enzyme protein concentration, while other types of steroids, such as testosterone, oestradiol and dexamethasone, were ineffective. The progestin-specific induction of 17-HSD was dose-related and was maximum in about 5 days. An antiprogestin, RU 486, when used in combination with synthetic progestins, blocked the progestin-induced increase of 17-HSD concentration very effectively. A good correlation was observed in the different experiments between the enzyme activity and the immunoreactive 17-HSD concentration. We conclude that progestins induce 17-HSD in T-47D cells and that the induction occurs via an increased accumulation of enzyme protein.
Int J Cancer 1990 Nov 15
PMID:Progestin induction of 17 beta-hydroxysteroid dehydrogenase enzyme protein in the T-47D human breast-cancer cell line. 222 18

In 28 cases of postmenopausal women with non-functioning ovarian tumors, the estradiol (E2) level was assayed in peripheral plasma and tumor tissue extract. E2 precursors were also assayed in the tissue extract, and localization of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) in the tissue was investigated. The plasma E2 levels were 153.8 +/- 205.9 pg/ml in 15 benign tumor cases, 244.3 +/- 336.5 pg/ml in 13 malignant tumor cases, and both of which were significantly higher than 12.3 +/- 3.6 pg/ml in normal postmenopausal women (p less than 0.01). The postoperative plasma E2 level (33.3 +/- 32.7 pg/ml) was significantly lower than the preoperative one (228.3 +/- 319.0 pg/ml). Twelve of 19 cases (68.2%) showed a postoperative decline in the E2 level to less than a half of the preoperative level. E2 and its precursors were found in tumor tissue. These findings demonstrate that E2 is produced by the tumor tissue itself. In addition, 3beta-HSD activity was localized in the stroma of ovarian tumors, indicating that E2 synthesis is mainly carried out in stromal cells rather than in epithelial cells.
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PMID:Estrogen producing activity in epithelial ovarian tumors and dermoid cysts. 262 80

We measured concentrations of cytosol and nuclear estrogen, as well as progestin receptors and activities of 17 beta-hydroxysteroid dehydrogenase (17-HSD), and examined histopathology and ultrastructure of endometrial carcinoma specimens taken before and after one-week danazol (200 mg, 3 times daily) or medroxyprogesterone acetate (MPA, 100 mg daily) treatments in 14 and 16 patients, respectively. A typical progestin effect, a significant increase in the activity of 17-HSD, was observed after both treatments. The post-therapy 17-HSD activities correlated significantly with the pretreatment cytosol progestin receptor concentrations in both treatment groups. Both MPA and danazol decreased the proliferative activity and increased the secretory activity of the malignant epithelial endometrial cells. These biochemical and morphological results support the concept that danazol has progestin-like actions on the human endometrium, and might therefore be an alternative for hormonal treatment of endometrial carcinoma.
Int J Cancer 1985 Feb 15
PMID:Short-term effects of danazol and medroxyprogesterone acetate on cytosol and nuclear estrogen and progestin receptors, 17 beta-hydroxysteroid dehydrogenase activity, histopathology, and ultrastructure of human endometrial adenocarcinoma. 315 97

We have previously shown that a stroma-associated paracrine influence may occur in the human breast. In particular, human breast fibroblasts secrete a factor which stimulates reductive 17 beta-oestradiol dehydrogenase (HSD) activity, thereby regulating tissue concentrations of 17 beta-oestradiol. We report here the results of experiments designed to establish the nature of the enzyme activity stimulating factor. In vitro cell culture techniques were used, in which human breast fibroblast-conditioned medium was used to grow the human breast cancer cell line, MCF-7, for 6 days, after which the reductive HSD activity of the monolayers was assessed. The fibroblastic reductive HSD stimulating factor was found to be a trypsin-sensitive polypeptide. The polypeptide eluted from a Sephadex G-75 column as a peak corresponding to a molecular weight of about 50 kDa. The polypeptide exerts its effects by altering the Vmax of 2 of the cytosolic forms of HSD within MCF-7 cells. This is achieved by a protein-synthesis-dependent but calmodulin-independent mechanism. These results provide further evidence of a paracrine effect by stromal tissue within the human breast and have important implications with respect to the aetiology and treatment of breast cancer.
Int J Cancer 1988 Jul 15
PMID:Paracrine influence of human breast stromal fibroblasts on breast epithelial cells: secretion of a polypeptide which stimulates reductive 17 beta-oestradiol dehydrogenase activity. 316 8

Significant but low concentrations (mean 8 fmol/mg cytosol protein) of cytosol estrogen receptors were found in 57% of non-diseased ovarian tissues, and higher concentrations (mean 211) of cytosol progestin receptors in all these tissues. An approximately similar distribution was found for the presence of nuclear female sex steroid receptors; the mean concentrations were 159 and 1149 sites/cell, for estrogen and progestin receptors, respectively. There were no major differences in these parameters between pre- and postmenopausal non-diseased ovaries. The activities of ovarian 17 beta-hydroxysteroid dehydrogenase (17-HSD) did not display correlations between circulating progesterone concentrations in pre- or postmenopausal women with non-diseased ovaries. The majority of benign epithelial tumors contained significant concentrations of cytosol estrogen receptors, and all showed cytosol progestin receptors. The concentration of estrogen receptors was identical to that seen in non-diseased ovaries (mean 9 fmol/mg cytosol protein), whereas that of progestin receptor was significantly lower (mean 95). Nuclear female sex steroid receptors were measured in all benign tumors, and their concentrations were significantly higher than in normal ovaries (440 and 3218 sites/cell for estrogen and progestin receptors, respectively). No difference in 17-HSD activities were detected between normal ovaries and benign tumors. In malignant ovarian tumors, the picture was different from that found in normal ovarian tissues and benign tumors. Cytosol estrogen receptor was found in 89% of malignant epithelial tumors, and its concentration was significantly higher (mean 64 fmol/mg cytosol protein). Cytosol progestin receptor was found in 91%, and its concentration (mean 75) was significantly lower than in normal ovarian tissue or benign ovarian tumors. Nuclear female sex steroid receptor concentrations were intermediate between those seen in non-diseased ovaries an in benign tumors. 17-HSD activity was significantly lower than in other tissue categories studied. In the small group (16) of non-epithelial ovarian carcinomas cytosol estrogen receptors were not found, whereas the results of other measurements did not display any coherent picture. Breast and endometrial carcinoma metastatic to the ovary showed receptor patterns which were typical of the primary tumors. When the different clinical stages (I-IV) of malignant epithelial ovarian tumors were compared, 17-HSD activity was significantly higher in the least advanced clinical stage (I), whereas no significant differences were found in the other parameters measured.(ABSTRACT TRUNCATED AT 400 WORDS)
Int J Cancer 1983 Oct 15
PMID:Cytosol and nuclear estrogen and progestin receptors and 17 beta-hydroxysteroid dehydrogenase activity in non-diseased tissue and in benign and malignant tumors of the human ovary. 631 58

Pathways of testosterone metabolism in tissue slices and cell suspensions of human benign hyperplastic prostate (BPH) tissue and human prostate cancer cell lines (DU145, HPC-36M, PC-3/MA2 and LNCaP) were investigated. Thin layer chromatography analysis was used to identify the following tritiated metabolites: testosterone, 5 alpha-dihydrostestosterone (DHT), 5 alpha-androstane-3 alpha/3 beta-17 beta-diol (androstanediols), 4-androstene-3,17-dione (androstenedione) and 5 alpha-androstanedione. The predominant pathway for testosterone metabolism in BPH was via 5 alpha-reductase producing 5 alpha-dihydrotestosterone (71% and 75% total metabolites in slices and suspensions incubated for 24 h, respectively). The cancer cell lines DU145 and HPC-36M resembled BPH by metabolizing testosterone predominantly to DHT (68% and 82% total metabolites, respectively), although the rate of metabolism was much lower in the cell lines (0.099 and 0.05 pmol testosterone/mg protein/h in DU145 and HPC-36M) compared to the BPH cell suspensions (6.4 pmol testosterone/mg protein/h). In contrast, PC-3/MA2 contained high 17 beta-HSD activity forming large amounts of 4-androstene-3,17-dione (84% total metabolites), converting testosterone at a rate faster (12.8 pmol testosterone/mg protein/h) than the BPH cell suspensions. LNCaP rapidly converted testosterone exclusively to a glucuronide conjugate (7.4 pmol testosterone/mg protein/h), although after incubation with [3H]-4-androstene-3,17-dione, 5 alpha-reductase activity was demonstrated. LNCaP was the only cell line whose growth and colony-forming ability was stimulated by testosterone and DHT. BPH and all the cell lines tested had 5 alpha-reductase activity, but only the prostate tissue and the cell lines DU145 and HPC-36M converted testosterone predominantly to DHT.
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PMID:Comparison of testosterone metabolism in benign prostatic hyperplasia and human prostate cancer cell lines in vitro. 751 39

Rat liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase (3 alpha-HSD/DD) is a member of the aldo-keto reductase gene superfamily. It displays high constitutive expression and inactivates circulating steroid hormones and suppresses the formation of polycyclic aromatic hydrocarbon anti- and syn-diol-epoxides (ultimate carcinogens). To elucidate mechanisms responsible for constitutive expression of the 3 alpha-HSD/DD gene a rat genomic library obtained from adult Sprague-Dawley female liver (HaeIII partial digest) was screened, using a probe corresponding to the 5'-end of the cDNA (-15 to +250), and a 15.8-kb genomic clone was isolated. Sequencing revealed that 6.3 kb contained exon 1 (+16 to +138 bp) plus additional introns and exons. The transcription start site (+1) was located by primer extension analysis, and the initiation codon, ATG, was located at +55 bp. The remaining 9.5 kb represented the 5'-flanking region of the rat 3 alpha-HSD/DD gene. A 1.6-kb fragment of this region was sequenced. A TATTTAA sequence (TATA box) was found at 33 bp upstream from the major transcription start site. cis-acting elements responsible for the constitutive expression of the rat 3 alpha-HSD/DD gene were located on the 5'-flanking region by transient transfection of reporter-gene (chloramphenicol acetyl transferase, CAT) constructs into human hepatoma cells (HepG2). CAT assays identified the basal promoter between (-199 and +55 bp), the presence of a proximal enhancer (-498 to -199 bp) which stimulated CAT activity 6-fold, the existence of a powerful silencer (-755 to -498 bp), and a strong distal enhancer (-4.0 to -2.0 kb) which increased CAT activity by 20-40-fold. A computer search of available consensus sequences for trans-acting factors revealed that a cluster of Oct-sites were uniquely located in the silencer region. Using the negative response element (-797 to -498 bp) as a probe and nuclear extracts from HepG2 cells, three bands were identified by gel mobility shift assay, indicating the presence of protein binding sites in this proposed negative response element. All three bands were supershifted with anti-Oct-1 mAb, suggesting that Oct-1 may be the repressor. The 5'-flanking region also contained an AP-1 site, an estrogen response element, and a glucocorticoid response element, which together may comprise a steroid response unit.(ABSTRACT TRUNCATED AT 400 WORDS)
Cancer Res 1995 Sep 15
PMID:Cloning, sequencing, and functional analysis of the 5'-flanking region of the rat 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase gene. 766 87


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