Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0276241 (MCF)
 28,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isoflavones and others phytoestrogens have been suggested to be anticarcinogenic. Anti-aromatase, antiestrogenic or antiproliferative actions of these compounds have been postulated and related to the observation that there is a reduced incidence of breast cancer associated with diet. In this study, we explored some mechanisms by which they can exert cancer-preventive effects. Phytoestrogens were tested for estimating anti-aromatase, anti-3beta-hydroxysteroid dehydrogenase delta5/delta4 isomerase (3beta-HSD) and anti-17beta-hydroxysteroid dehydrogenase (17beta-HSD) activities in human placental microsomes. We found that isoflavonoids and compounds which presented the phenolic B ring in the 3 position on the pyran ring preferentially inhibited 3beta-HSD and/or 17beta-HSD activities than aromatase activity. We also evaluated their interactions with the estrogen receptor using a stably transfected human breast cancer cell line (MVLN). On the other hand phytoestrogens were evaluated for their effects on the proliferation in estrogen-dependent (MCF-7) and independent (MDA-MB231) human breast cancer cells. We established a relationship structure-activity and determined regions or/and substituents essential for these different activities. However, at high concentrations it seems that some phytoestrogens exert their protection against breast cancer through other estrogen-independent mechanisms.
 ...
PMID:Effects of phytoestrogens on aromatase, 3beta and 17beta-hydroxysteroid dehydrogenase activities and human breast cancer cells. 1075 63

The estrogen receptor (ER)-positive MCF-7 breast cancer cell line can be transplanted into athymic mice and grown into tumors with estradiol (E2) support. Tamoxifen (TAM) blocks E2-stimulated tumor growth; however, continuous TAM treatment results in transplantable tumors within a year that will grow with either E2 or TAM (M. M. Gottardis and V. C. Jordan, Cancer Res., 48: 5183-5187, 1988). Although this model may represent the development of TAM resistance for the treatment of advanced breast cancer, no laboratory model exists to study the exposure of breast cancer to 5 years of adjuvant TAM therapy. We have addressed this issue and report the development and characterization of two tumor lines, MCF-7TAM and MT2, which have been serially transplanted into TAM-treated athymic mice for >5 years. The MCF-7TAM tumor rapidly regresses in response to E2 and then about 50% of tumors regrow in response to E2. Interestingly, tumor regression does not occur if TAM treatment is stopped, probably because E2 levels are too low in ovariectomized athymic mice. The development of the antitumor effect of E2 was documented for MT2 tumors over a 1-year period; TAM-stimulated tumor growth was retained, but E2 caused progressively less of a stimulatory effect. Most importantly, E2-stimulated tumors that regrew after initial tumor regression in both MCF-7TAM and MT2 lines were again responsive to TAM to block E2-stimulated growth. Unlike MCF-7 tumors, the MT2 tumor line contains a single point mutation, Asp351Tyr, in the ER, which was retained after the development of E2-stimulated regrowth. The mutation is associated with increased estrogen-like actions for the TAM-ER complex (A. S. Levenson et al., Br. J. Cancer, 77: 1812-1819, 1998), but we conclude that the mutant ER is not required for TAM resistance. On the basis of the new breast cancer models presented, we propose a cyclic sensitivity to TAM that may have important clinical implications: (a) it is possible that a woman's own estrogen may produce an antitumor effect on the presensitized micrometastatic disease after 5 years of TAM. Long-term antitumor action occurs because the drug is stopped, but resistance accumulates and tumors start to grow if adjuvant therapy is continued; and (b) although in the clinic TAM-resistant tumors respond to second-line therapies that cause estrogen withdrawal, e.g., pure antiestrogens or aromatase inhibitors, estrogen therapy may also be effective and return the tumor to TAM responsiveness. In this way, a hormone-responsive tumor may be controlled longer in the patient with advanced disease.
 ...
PMID:Antitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice. 1081 29

The interaction between the estrogen receptor and 5-hydroxy-7-methoxyflavanone (pinostrobin) was studied in the presence or absence of estradiol or dehydroepiandrosterone sulfate (DHEAS), respectively, using a stably transfected human breast cancer cell line (MVLN). We also evaluated its action on the proliferation in estrogen-dependent (MCF-7) human breast cancer cells in the same conditions than the estrogen receptor assay. On the other hand pinostrobin was evaluated for their effects on the human placental aromatase, 3beta-hydroxysteroid dehydrogenase Delta(4)/Delta(5) isomerase and 17beta-hydroxysteroid dehydrogenase activities. Pinostrobin did not possess antiestrogenic activity but presented anti-aromatase activity and decreased the growth of MCF-7 cells induced by DHEAS and E(2). This study provides particularly evidence of the potential biological interest of pinostrobin among the flavonoids.
 ...
PMID:Effects of pinostrobin on estrogen metabolism and estrogen receptor transactivation. 1084 Jan 57

The effect of the chemopreventive synthetic retinoid N-(4-hydroxyphenyl)-retinamide (4-HPR) on aromatase activity and expression was examined. 4-HPR caused a dose-dependent inhibition of aromatase activity in microsomes isolated from JEG-3 human placental carcinoma cells. The kinetics of inhibition were analysed by double-reciprocal plot. The Km of the substrate increased and the Vmax of the reaction decreased in the presence of 4-HPR, indicating that enzyme inhibition involved both competition for the substrate-binding site and non-competitive mechanisms. To determine whether 4-HPR would also inhibit aromatase activity in intact cells, MCF-7 human breast cancer cells were incubated with or without cAMP in the presence of 4-HPR. 4-HPR inhibited both basal and cAMP-induced aromatase activity in intact MCF-7 cells. The induction of aromatase mRNA expression in MCF-7 cells by cAMP was inhibited in cells treated with 4-HPR. These results indicate that 4-HPR inhibits both the enzymatic activity and expression of aromatase. These activities may play an important role in the known chemopreventive effect of 4-HPR towards breast cancer.
 ...
PMID:Inhibition of aromatase activity and expression in MCF-7 cells by the chemopreventive retinoid N-(4-hydroxy-phenyl)-retinamide. 1091 48

Estrogen is the most important endocrine hormone that stimulates the growth of hormone-dependent breast cancer. The biosynthesis of estrogens in breast tissue is catalyzed by cytochrome P450 aromatase (P450arom). The expression of P450arom is controlled by the tissue- or cell-specific promoters of CYP 19 gene. The roles of nuclear receptor systems for the aromatase activity in breast cancer cells have not yet been fully investigated. In the present study, we investigated the effects of a nuclear receptor system constituted by retinoid X receptor (RXR) and its heterodimer partner on the aromatase activity in a cultured MCF-7 human breast cancer cell line, using each selective ligand for retinoic acid receptor (RAR) (TTNPB), RXR (LG100268), PPARgamma (troglitazone), and vitamin D(3) receptor (vitamin D(3)). The treatment of the cells with TTNPB or LG100268 alone for 2 days increased slightly the aromatase activity, but the increases were not statistically significant in comparison to the control. However, the combined treatment with TTNPB (10(-7) M) and LG100268 (10(-7) M) caused a dramatic stimulation of the aromatase activity. The treatment with other ligands had little or no effect on the aromatase activity. The stimulation of the aromatase activity by TTNPB plus LG100268 was dose-dependent, and a maximum stimulation was observed at 10(-7) M in both compounds. In addition, the increase in the aromatase activity was accompanied by an increase in the P450arom mRNA levels determined by RT-PCR in MCF-7 cells. The increase in the P450arom transcript was also found to be related to the specific usage of promoter 1a of the CYP 19 gene based on the analysis using RT-PCR. This is the first demonstration that a nuclear receptor system constituted by a RAR:RXR heterodimer is involved in the regulation of aromatase activity in MCF-7 breast cancer cells.
 ...
PMID:A nuclear receptor system constituted by RAR and RXR induces aromatase activity in MCF-7 human breast cancer cells. 1099 32

Steroid sulfatase (STS) regulates the formation of active steroids from systemic precursors, such as estrone sulfate and dehydroepiandrosterone sulfate (DHEAS). In breast tissues, this pathway is a source for local production of estrogens, which support the growth of endocrine-dependent tumours. Therefore, inhibitors of STS could have therapeutic potential. In this study, we report on substituted chromenone sulfamates as a novel class of non-steroidal irreversible inhibitors of STS. The compounds are substantially more potent (6- to 80-fold) than previously described types of non-steroidal inhibitors when tested against purified STS. In MCF-7 breast cancer cells, they inhibit STS activity with IC(50) below 100 pM. Importantly, the compounds also potently block estrone sulfate-stimulated growth of MCF-7 cells, again with IC(50) below 100 pM. For one compound, we also observed a lack of any estrogenic effect at high concentrations (1 microM). We also demonstrate for the first time that STS inhibitors can block the DHEAS-stimulated growth of MCF-7 cells. Interestingly, this cannot be achieved with specific inhibitors of the aromatase, suggesting that stimulation of MCF-7 cell growth by DHEAS follows an aromatase-independent pathway. This gives further justification to consider steroid sulfatase inhibitors as potential drugs in the therapy of breast cancer.
 ...
PMID:Stimulation of MCF-7 breast cancer cell proliferation by estrone sulfate and dehydroepiandrosterone sulfate: inhibition by novel non-steroidal steroid sulfatase inhibitors. 1107 Mar 51

Estrogen receptor (ER)-positive breast cancers initially respond well to estrogen ablation treatment but finally acquire refractoriness, the phenomenon that is a major clinical problem. Because some breast cancers synthesize estradiol (E(2)) and E(2) synthesis is regulated by gonadotropins in normal ovaries, and because circulating gonadotropins are elevated in postmenopausal women and during estrogen ablation treatment, we hypothesized that gonadotropins might modulate estrogen synthesis/metabolism in breast cancer tissue as well. To test this possibility, MCF-7 cells were treated with dehydroepiandrosterone (DHEA) or human chorionic gonadotropin (hCG; approximately LH), each alone or in combination. Cell growth (3-day treatment) was assayed by the MTT method and estrogen synthesis (24-hour treatment) was measured using the ERE-luciferase reporter system. First, MCF-7 cell growth was stimulated by DHEA in a concentration-dependent manner with a maximal effect at 10(-4) M. Although hCG alone did not have a significant proliferative effect, hCG significantly and dose dependently stimulated MCF-7 cell growth in the presence of a submaximal concentration of DHEA (10(-7 )M). This stimulatory effect of DHEA and hCG was blocked by a pure antiestrogen ICI182,780 and an aromatase inhibitor, arimidex. Using MCF-7 cells transfected with the ERE-luciferase reporter system, hCG treatment was shown to increase ERE-mediated transcription. These results indicate that MCF-7 cells intrinsically converted DHEA into E(2) upon hCG stimulation, then grew their own cells DHEA- and hCG-dependently. We conclude that gonadotropins can act on breast cancer cells and accelerate conversion of DHEA into estrogens, thereby stimulating growth of estrogen-dependent tumor cells. This phenomenon, at least in part, could explain: (1) an increased tissue concentration of E(2) in postmenopausal breast cancer; (2) acquisition of hormone refractoriness during estrogen ablation treatment, and (3) the effectiveness of GnRH antagonist/superagonist in some postmenopausal breast cancer patients.
 ...
PMID:Gonadotropins stimulate growth of MCF-7 human breast cancer cells by promoting intracellular conversion of adrenal androgens to estrogens. 1109 52

The racemate compound MEN 11066 (1-[(benzofuran-2-yl)(4'-cyanophenyl)methyl]-1H-1,2,4-triazole) and its enantiomers, (+)-MEN 11623 and (-)-MEN 11622, showed potent and selective aromatase activity on human placental microsomes. In addition, to better evaluate their potency as anticancer drugs, the compounds were assayed on testosterone-induced cell proliferation to measure their ability in inhibiting oestrogen-dependent tumour growth. Two different sublines originated from the human breast carcinoma MCF-7 were used. One, named MCF-7(tumour aromatase) (TA), that had maintained its intrinsic aromatase activity, was more sensitive to estradiol or testosterone-induced growth than the second subline named MCF-7(human placental aromatase) (hPA). The latter had been transfected with the human placental aromatase cDNA, after recognizing that the parental cells had aromatase activity reduced to undetectable levels. The MEN compounds completely reverted the testosterone-induced proliferation in both MCF-7(TA) and MCF-7(hPA) cells, while they did not affect the estradiol-triggered proliferation as a proof of their specificity for aromatase enzyme. Interestingly, MCF-7(TA) cells were more susceptible to the effects of aromatase inhibitors than the MCF-7(hPA) cell. These data suggest the efficacy of aromatase inhibitors in breast cancer when the growth dependency from oestrogen is high and a relatively low aromatase activity may be extremely important for tumour development.
 ...
PMID:Effect of the aromatase inhibitor, MEN 11066, on growth of two different MCF-7 sublines. 1110 22

Dehydroepiandrosterone (DHEA) is a mitogen for estrogen-dependent MCF-7 breast cancer cells. Our aims were to determine whether DHEA required conversion to estrogens in order to stimulate cell proliferation and estrogen-dependent gene expression. After incubation of cells with 100 nM DHEA for 4 days, estradiol was present in the medium at a concentration of approximately 200 pM. Other compounds identified were testosterone ( approximately 300 pM) and estrone. Significant stimulation of cell proliferation by 1 nM estradiol and 100 nM DHEA was observed after 38 h and 4 days of incubation, respectively, indicating the necessity of DHEA conversion. DHEA doses > or = 10 nM induced estrogen-dependent reporter gene expression in MCF-7 cells transfected with a luciferase reporter gene under the control of the estrogen response element. DHEA-dependent stimulation of proliferation and luciferase induction could be inhibited by the anti-estrogens ICI182,780 and tamoxifen, respectively, and by the aromatase inhibitor 4-hydroxyandrostenedione. An androgenic effect of DHEA on proliferation and gene expression of MCF-7 cells was not observed. We conclude that conversion of DHEA to estrogens, particularly estradiol, is required to exert a mitogenic response.
 ...
PMID:Dehydroepiandrosterone stimulates proliferation and gene expression in MCF-7 cells after conversion to estradiol. 1122 73

Aromatase is an enzymatic complex responsible for the conversion of androgens into estrogens; these hormones are important in development, reproduction, but also in the growth of estrogen-dependent cancer. This enzyme is present in 60-70% of the breast cancer. The aromatase inhibitors are important drugs in the breast cancer treatment of postmenopausal women. In order to study their in vivo activity, animal models have been developed, e.g. rat with tumour induced by 7,12-dimethylbenz[a]anthracene, PMSG-primed immature rat or athymic nude mice with aromatase transfected MCF-7 xenograft. In this review, we were interested in preclinical results obtained with both classes: steroidal and nonsteroidal inhibitors. The former group, as substrate analogs formestane or exemestane, are irreversible, selective and long-lasting inhibitors of aromatase. The nonsteroidal molecules, such as letrozole or anastrozole, are reversible inhibitors with high affinity. Finally, knowledge of the enzyme active site, with molecular modeling and site-directed mutagenesis, could be useful to develop new inhibitor families, more specific and potent in vivo.
 ...
PMID:[Preclinical evaluation of aromatase inhibitors antitumor activity]. 1125 Jun 4


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