Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various flavonoids, such as genistein, luteolin, and coumestrol, have actions in mammals that are mediated by binding either to classical estrogen receptors or to type II receptors, which also bind estrogen. These actions are of intense interest because they may be the basis for the protective actions of plants against certain cancers, such as breast cancer. The biological activity of flavonoids in mammals raises some questions. Is the hormonal action of flavonoids "an accident" derived from their phenolic groups and general hydrophobicity, which gives them some properties in common with estrogens? Or do flavonoids regulate gene transcription in other organisms? And, if so, is there a connection between their actions in these organisms and in mammals? Some answers to these questions are provided by the actions of plant-derived flavonoids in regulating gene transcription in rhizobia, bacteria that form nitrogen-fixing nodules in the roots of legumes, which has several interesting similarities with steroid-mediated actions in vertebrates. First, there is specificity in the actions of flavonoids in rhizobia; oxidation or reduction of the flavonoid or removal of a hydroxyl group can alter its biological activity. Moreover, some flavonoids are anti-inducers functioning like steroid antagonists to negate the actions of inducers. Also there are sequence similarities between various steroid metabolizing enzymes and proteins found in rhizobia, which indicates that these proteins are derived from a common ancestor. For example, 17 beta-hydroxysteroid dehydrogenase, which catalyzes the interconversion of the alcohol and ketone a C17 on estrogens and androgens, 11 beta-hydroxysteroid dehydrogenase, which catalyzes the interconversion of the alcohol and ketone at C11 of glucocorticoids, and 3 alpha,20 beta-hydroxysteroid dehydrogenase, which catalyzes the interconversion of the alcohol and ketone at C20 of corticosteroids, are homologs of proteins found in rhizobia. Thus, the binding of flavonoids to vertebrate proteins may represent an evolutionary linkage between the actions of steroids in mammals and communication between plants and rhizobia.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Evolution of regulation of steroid-mediated intercellular communication in vertebrates: insights from flavonoids, signals that mediate plant-rhizobia symbiosis. 156 8

The control of human breast cancer cell proliferation in vitro is known to involve complex interactions between steroid hormones, peptide hormones and growth factors. Little is known, however, of the mechanisms by which these factors, alone or in combination, control cell cycle progression and the expression of specific genes involved in cell cycle control. A pre-requisite for such studies is a cellular system in which non-proliferating or slowly proliferating cells can be maintained in a defined environment and stimulated to progress through the cell cycle by addition of hormones and growth factors. Such a system has been developed for T-47D human breast cancer cells: quiescent or slowly proliferating cells maintained in a serum-free medium can be stimulated to increase their rate of cell cycle progression upon a single addition of insulin, IGF-I, EGF, TGF alpha or bFGF. Oestradiol alone was ineffective but caused a significant increase in % S phase cells when added in the presence of insulin. Progestins, in the presence of absence of insulin, had a biphasic effect with an initial increase in cell cycle progression followed by cell cycle arrest. Both antioestrogens and the antiprogestin, RU 486, in the absence of oestrogen or progestin, were potent inhibitors of insulin-induced proliferation. Increases in cell cycle progression were invariably accompanied by acute increases in c-fos and c-myc mRNA levels. Induction of c-myc by oestrogen and progestin was inhibited by antioestrogens and RU 486, respectively. These data illustrate that the culture of breast cancer cells in a serum-free, chemically defined environment provides an excellent model in which to define the role of individual factors involved in breast cancer growth control. The biological data derived from this system provide a basis for identifying and characterizing genes involved in the control of cell cycle progression in human breast cancer.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Regulation of breast cancer cell cycle progression by growth factors, steroids and steroid antagonists. 156 9

A new approach for the treatment of breast cancer could be the use of progesterone antagonists. These compounds were originally developed for the inhibition of progesterone-dependent processes and have been shown to be effective in inhibition of nidation and interruption of pregnancy. Although the roles of progesterone and the progesterone receptor in control of cell growth remain unclear, it was found in progesterone receptor positive mammary carcinoma cell lines that the antiprogestin, Mifepristone, had an inhibitory effect on cell growth and a growth-inhibiting action on the DMBA-induced mammary carcinoma of the rat. We have shown that the progesterone antagonists, Onapristone and ZK 112993, which possess a reduced antiglucocorticoid activity compared to Mifepristone, exert a strong tumor-inhibiting effect in a panel of hormone-dependent mammary tumor models. The effects of these compounds were in some systems superior to those of tamoxifen or high dose progestins and comparable to ovariectomy. Although prerequisites for their antiproliferative potency are an affinity to the progesterone receptor as well as a sufficient number of available receptors in the tumors, the strong tumor inhibiting potential of the antiprogestins cannot be explained by a classical anti-hormonal mechanism. Surprisingly, the antitumor activity is evident in spite of elevated serum levels of ovarian and pituitary hormones. It was established by morphometric procedures that treatment with Onapristone triggers differentiation of the mitotically active polygonal tumor epithelial cell towards secretory active glandular structures and acini. All our quantitative light and electron microscopic data indicate that the antitumor action of antiprogestins is accompanied by the initiation of terminal differentiation leading to (apoptotic) cell death. Finally, our flow cytometry studies revealed an accumulation of the tumor cells in the G0G1 phase of the cell cycle, which may result from induction of differentiation since a differentiation-specific G1 arrest has already been proposed for other stem cell systems. It can be concluded from these data that the progesterone receptor antagonists differ in their mode of action from compounds used in established endocrine treatment strategies for mammary carcinoma. The ability of progesterone antagonists like Onapristone to reduce the number of cells in S-phase may offer a significant clinical advantage, since it is established that the S-phase fraction is a highly significant predictor of disease-free survival among axillary node-negative patients with diploid mammary tumors.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Progesterone antagonists: tumor-inhibiting potential and mechanism of action. 156 10

The mechanisms underlying loss of oestrogen responsiveness in breast cancer are not well-defined. Potential mechanisms include loss of receptor expression, alterations in the oestrogen receptor (ER) gene producing proteins with abnormal function, or changes to receptor-dependent or -independent pathways controlling cell proliferation. Examination by Southern analysis of the ER gene in a series of ER-negative and -positive breast tumour biopsies failed to provide evidence of gross rearrangements and in only one of thirty seven tumour DNA samples was significant gene amplification observed. No restriction fragment length polymorphisms were detected for the restriction enzymes EcoR I, Pst I or Hind III. Methylation of the ER gene as assessed by Hpa II and Msp I restriction enzyme digests varied between tumours but the degree of methylation was not correlated with levels of expression of the receptor protein. Similar findings applied in a series of ER-negative and -positive breast cancer cell lines and clonal lines of MCF-7 cells, which were developed as an in vitro model for the acquisition of oestrogen and antioestrogen resistance. In this model there was no evidence that changes to ER receptor function and/or structure at the level of the ER gene, mRNA, ligand binding, and ability to induce progesterone receptor might account for the development of hormone resistance. However, the ability of ER to interact with a DNA sequence containing the vitellogenin promoter oestrogen response element, as assessed by gel retardation assay, was impaired in the clone showing the greatest degree of oestrogen and antioestrogen resistance.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Oestrogen receptor gene structure and function in breast cancer. 156 23

In the present study, we explore the effect of the cellular extracts and culture medium of the embryonic mouse cell line BALB/c-3T3 (clone A31) on the proliferation and DNA content of the human T-47D breast cancer cell line. These effects were also studied in the presence of the potent anti-estrogen ICI 164,384. All experiments were prepared in MEM medium containing 5% fetal calf serum treated with dextran charcoal, as well as the homogenization of the BALB/c-3T3 cells to obtain the cellular extract. Aliquots of cellular extracts (2%) corresponding to 2 x 10(6) cells, or culture medium (16%), are incubated with the T-47D cells. After 9 days of culture, cellular extracts and culture medium provoke an intense proliferative effect corresponding respectively to 2 and 5 times the control value of T-47D cells. These effects on cell proliferation are correlated with DNA content. Although the anti-estrogen ICI 164,384 (5 x 10(-8) M) alone decreases the proliferation of T-47D cells by half, the presence of the culture medium from the BALB/c-3T3 cells abolishes this effect and, on the contrary, increases the cell proliferation 4-fold. It is concluded that mouse embryonic cells (BALB/c-3T3) contain factor(s) which stimulate very intensively the proliferation of hormone-dependent T-47D mammary cancer cells. This factor(s) is present in both the cell and the culture medium and can antagonize the anti-proliferative effect of the anti-estrogen ICI 164,384.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Effect of embryonic mouse cells BALB/c-3T3 on the proliferation of the human mammary cancer cell line T-47D. 156 26

A number of 2-(4-hydroxyphenyl)benzo[b]thiophenes with a hydroxy group in position 5 or 6 and a short alkyl group at C-3 were synthesized and studied for their estrogen receptor affinities. Relative binding affinities (RBA) for the calf uterine estrogen receptor ranged from 3 to 60 (17 beta-estradiol = 100). The highest RBA values were found with ethyl derivatives [3 (5-OH): 60; 7 (6-OH): 28]. In accord with their receptor affinity, all benzothiophenes exhibited endocrine activity in the immature mouse uterine weight test. At doses of 0.25-7.0 mg/kg body weight, they showed partial estrogen antagonism and usually weak estrogenic effects. All compounds entered tests with hormone-sensitive human MCF-7 breast cancer cells. At concentrations of 1 microM and higher, most of the derivatives displayed significant inhibition of cell growth. These results prompted us to test them in vivo for cytostatic activity using hormone-dependent MXT mouse mammary tumors. The 5-hydroxy derivatives 3 and 4 strongly inhibited the growth of these tumors. After 4 weeks of treatment with 3 x 4.2 mg/kg of compound 3, the average tumor weight was reduced by 83% vs control (tamoxifen at equimolar dose: 74%). The 6-hydroxy derivative 7 required higher doses (25 mg/kg) to give rise to the same antitumor effect. At the end of therapy, no increase of uterine weight due to an estrogenic effect was observed. We assume therefore that the antineoplastic activity of these compounds in this tumor model is due mainly to their estrogen antagonism.
J Steroid Biochem Mol Biol 1992 Mar
PMID:3-Alkyl-2-phenylbenzo[b]thiophenes: nonsteroidal estrogen antagonists with mammary tumor inhibiting activity. 156 27

Currently there is much interest in the role that growth factors may play in the development of human breast tumours. We have shown previously that growth factors secreted by breast tumours may influence the activity of oestradiol hydroxysteroid dehydrogenase, the enzyme which catalyses the interconversion of oestrone (E1) and oestradiol. As the formation of E1 from its sulphate (E1S) by oestrone sulphatase may be quantitatively more important than production from androstenedione via aromatase, we have studied the effect of insulin-like growth factor-1 (IGF-I) and basic fibroblast growth factor (bFGF) on oestrone sulphatase activity in the hormone-dependent MCF-7 and the hormone-independent MDA-MB-231 breast cancer cell lines. In both these cell types, bFGF (1-200 ng/ml) and IGF-I (25-200 ng/ml) significantly stimulated oestrone sulphatase activity in a dose-dependent manner (by 8-60%) after 48 h. Additionally, cycloheximide significantly inhibited (by 90-120%) this stimulation of oestrone sulphatase activity by the two growth factors in both MCF-7 and MDA-MB-231 cells. Basal oestrone sulphatase activity was higher in the oestrogen receptor, ER-ve MDA-MB-231 cells than in the ER + ve MCF-7 breast cancer cells. We conclude that these growth factors, believed to be secreted by breast tumours, may induce enzymes of oestrogen synthesis and hence increase local production of oestrogens.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Modulation of oestrone sulphatase activity in breast cancer cell lines by growth factors. 156 28

The non-aromatizable androgen dihydrotestosterone (DHT) has been shown to exert a potent inhibitory effect on the proliferation of some human breast cancer cell lines. DHT, however, has little or no significant inhibition on MCF-7 cell proliferation in either the presence or absence of estradiol (E2). Since the metabolism of DHT into non-active compounds may be responsible for the observed lack of androgenic effect in this cell line, we have investigated the metabolic fate of labeled DHT in MCF-7 cells. A time course incubation was performed with 1 nM [3H]DHT and analysis of the various metabolites formed revealed a time-dependent increase in glucuronidated steroids which was stimulated more than 4-fold by 0.1 nM E2. The major glucuronidated steroid was androstane-3 alpha, 17 beta-diol in both control and E2-stimulated cells, comprising 22 +/- 1.2% and 30 +/- 0.6% of the total radioactivity in the medium, respectively. Other steroid glucuronides observed included DHT, androstane-3 beta,17 beta-diol, and androsterone, all of which were elevated in the E2-treated cells relative to control values. The present data show that E2 exerts a stimulatory effect on the glucuronidation of androgens and their metabolites in the estrogen-dependent breast cancer cell line MCF-7. Since glucuronidation is an effective means of cellular elimination of active steroids, such a pathway may be considered as a possible site of regulation of breast cancer cell growth by hormones.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Estrogen-stimulated glucuronidation of dihydrotestosterone in MCF-7 human breast cancer cells. 156 29

The endometrial stroma plays a decisive role in sustaining the gland epithelium along the menstrual cycle, and in preparing the microenvironment that allows embryo implantation. The stroma undergoes important changes during the menstrual cycle that affects both the cell number and differentiation. These changes are regulated by both estrogen and progesterone. Stromal sarcomas are extremely rare, occurring much less than any other uterine tumor. Their origin and biology are poorly understood. The purpose of this work was to try to learn more about the stromal physiology, and also to ascertain whether the stromal sarcoma has characteristics of hormone dependence. We studied the presence of estrogen receptors (ER), progesterone receptors (PR) and the stress-responsive protein of 27K (srp27, a protein first described as an estrogen-induced 24K protein in MCF-7 cells) in both normal stroma and stromal sarcoma. The ER and PR were measured by exchange assays. The srp 27 was studied both by Western-blot and by IHC by means of specific monoclonal antibodies. The stromal sarcomas studied showed a high concentration of both ER (96 to 116 fmol/mg prot.) and PR (565 to 995 fmol/mg prot.). These amounts of ER and PR were higher than the mean found in normal endometrium during the proliferative phase (43 and 637 fmol/mg prot., respectively), and much higher than that of the secretory phase (17 and 229 fmol/mg prot., respectively). The srp27 characterized by Western-blot in both the normal stroma and stromal sarcoma was found to be similar to the srp27 of breast cancer. The IHC results showed a very low expression of srp27 in the stroma during the proliferative phase that increases when the endometrium enters the secretory phase. The low-malignancy grade stromal sarcomas showed abundant expression of srp27, but the high-malignancy grade sarcomas showed no expression of srp27. The obtained results prove the stroma capability to express the srp27. A negative correlation between malignancy of stromal tumors and srp27 expression was found. The presence of ER and PR in some stromal sarcomas proves that they have characteristics of hormone responsiveness. These findings suggest that ER and PR assays should be routinely performed in stromal sarcomas as well as in endometrial adenocarcinomas, and also that antiestrogenic drugs might be considered for the treatment of ER and PR positive stromal sarcomas.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Endometrial stromal sarcoma expression of estrogen receptors, progesterone receptors and estrogen-induced srp27 (24K) suggests hormone responsiveness. 156 30

In order to find new antiestrogens, devoid of any agonistic activity, a series of 11 beta-amidoalkyl estradiols were prepared. These compounds have been studied in comparison with tamoxifen (TAM): in vitro, for their relative binding affinities (RBA) for mouse and MCF-7 estrogen receptors (ER) and for their antiproliferative effect on MCF-7 (estradiol or EGF/PDGF stimulated) and Ly2 human breast cancer cell lines; in vivo, for their uterotrophic/antiuterotrophic activities in the mouse and for their antitumoral activities on MCF-7 tumors implanted in nude mice. The most representative compounds are N-methyl-N-isopropyl-(3,17 beta-dihydroxy-estra-1,3,5(10)-trien-11 beta-yl)- undecanamide (RU 51625) and its 17 alpha-ethynyl derivative (RU 53637). They showed good RBAs for ER and a stronger antiproliferative effect than TAM in vitro. Unlike TAM, these compounds inhibited growth factor stimulated MCF-7 proliferation, and the growth of the TAM resistant cell line Ly2. In vivo, they were completely devoid of uterotrophic activity, when given subcutaneously in mice, but exhibited a slight agonistic effect when administered orally. They showed interesting antitumor activities in nude mice by the percutaneous route, but RU 53637 was significantly more potent than RU 51625 when given orally.
J Steroid Biochem Mol Biol 1992 Mar
PMID:11 beta-amidoalkyl estradiols, a new series of pure antiestrogens. 156 31


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>