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

---

Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinoids have antiproliferative effects in human breast cancer cells and share some characteristics with antiestrogens, although the molecular targets involved have yet to be identified in either case. Using T-47D human breast cancer cells, we compared the effects of retinoic acid (RA) and the antiestrogen ICI 164384 on cell cycle phase distribution and the expression of genes with known functions in cell cycle control. Both RA and ICI 164384 inhibited cell cycle progression in G1 phase, but the RA effect was delayed by 16 h. This delay in action was also seen with 9-cis RA and other retinoids. Administration of 17 beta-estradiol abolished the effects of ICI 164384 but was without effect in RA-treated cells. Antiestrogen treatment caused a rapid inhibition of c-myc and cyclin D1 gene expression and reduced Cdk2 activity by more than 50% at 24 h. RA, however, did not affect c-myc or cyclin D1 gene expression, nor did it significantly change the mRNA or protein levels of cyclins D3 or E or cyclin-dependent kinases (CDK) Cdk2 or Cdk4. RA-induced reduction in Cdk2 activity was modest and occurred after %S phase declined, while Cdk4 activity was reduced, coincident with cell cycle changes. However, following either RA or ICI 164384, there was a reduction in the amount of hyperphosphorylated pRB, first apparent well before cell cycle changes were seen. These data demonstrate that: (a) the mechanisms of action of antiestrogens and retinoids are different but converge at pRB; and (b) RA can affect CDK activity without reducing cyclin or CDK levels.
...
PMID:Differential effects of retinoids and antiestrogens on cell cycle progression and cell cycle regulatory genes in human breast cancer cells. 878 34

Estrogen responses of human breast cancer cell lines have frequently been shown to be promoted by insulin. We have examined the action of insulin, and its interaction with estradiol, in regulating the expression of the estrogen-induced genes, LIV-1 and pS2. Both hormones cause increases in mRNA levels of the two genes but do so by distinct mechanisms. The concentration of insulin required to produce this effect suggests that it is acting via its ability to bind to the IGF-1 receptor. Both insulin and estradiol exert their effects at the level of transcription. Induction by insulin is dependent upon continued protein synthesis whereas induction by estradiol is not. Induction by both insulin and estradiol is prevented by the pure antiestrogen. ICI 164384, indicating the requirement for an activatable estrogen receptor. Insulin does not stimulate LIV-1 expression via the androgen receptor. These results demonstrate that both estradiol and insulin can stimulate the transcription of these estrogen-inducible genes, by separate mechanisms both of which involve the estrogen receptor.
...
PMID:Insulin/IGF-1 modulation of the expression of two estrogen-induced genes in MCF-7 cells. 886 63

Both retinoids and anti-estrogens inhibit breast cancer cell proliferation with accumulation of cells in the G1 phase of the cell cycle, but the effect of retinoids is delayed compared to that of anti-estrogens. To determine whether this temporal difference is due to a simple delay in the action of retinoids on a common site or to different sites of action within the G1 phase, we studied the cell cycle effects of retinoic acid (RA) and the anti-estrogen ICI 164384 (ICI) in T-47D cells partially synchronized by mevalonic acid rescue of lovastatin-induced cell cycle arrest. We found that cells entering the cell cycle semi-synchronously after mevalonic acid rescue of lovastatin treatment were immediately susceptible to ICI but not RA. This suggests that RA may act at a point up-stream and ICI at a point down-stream of lovastatin action. Consistent with this, cells recommencing cell cycle progression after RA treatment were susceptible to the effects of lovastatin, while cells pre-treated with ICI then rescued with estradiol were not. In addition, cells rescued from cell cycle arrest induced by either RA, ICI or lovastatin entered S phase with the same kinetics. Our findings suggest, first, that within G1, RA acts before and ICI acts after the point of lovastatin action and, second, that despite these differences in the initiation of cell cycle arrest, the final nature of the cell cycle arrest is similar. Hence, retinoids and anti-estrogens may be expected to target different cell cycle-regulatory molecules to initiate cell cycle arrest, while overcoming this arrest may be accomplished by the activation of a common molecular pathway.
...
PMID:Different points of action of retinoids and anti-estrogens in G1 phase identified in synchronized T-47D breast cancer cells. 903 30

Since estrogens play a predominant role in the development and growth of human breast cancer, antiestrogens represent a logical approach to the treatment of this disease. The present study compares the effects of the novel nonsteroidal anti-estrogen EM-800 and related compounds with those of a series of anti-estrogens on basal and 17 beta-estradiol (E2)-induced cell proliferation in human breast cancer cell lines. In the absence of added E2, EM-800 and related compounds failed to change basal cell proliferation, thus showing the absence of intrinsic estrogenic activity in the ER-positive T-47D, ZR-75-1 and MCF-7 cell lines. The stimulation of T-47D cell proliferation induced by 0.1 nM E2 was competitively blocked by a simultaneous incubation with EM-652, EM-800, OH-tamoxifen, OH-toremifene, ICI 182780, ICI 164384, droloxifene, tamoxifen and toremifene at apparent Ki values of 0.015, 0.011-0.017, 0.040-0.054, 0.043, 0.044, 0.243 and 0.735 nM, approx. 10 nM and > 10 nM, respectively. Similar data were obtained in ZR-75-1 and/or MCF-7 cells. Moreover, EM-652 was 6-fold more potent than OH-Tamoxifen in inhibiting the proportion of cycling MCF-7 cells. Our data show that EM-800 and EM-652 are the most potent known antiestrogens in human breast cancer cells in vitro and that they are devoid of the estrogenic activity of OH-tamoxifen and droloxifene suggested by stimulation of cell growth in the absence of estrogens in ZR-75-1 and MCF-7 cells.
...
PMID:Characterization of the effects of the novel non-steroidal antiestrogen EM-800 on basal and estrogen-induced proliferation of T-47D, ZR-75-1 and MCF-7 human breast cancer cells in vitro. 933 16

Estrogen (E) inhibits the growth of both non-tumorigenic, immortal human mammary epithelial cells (HMEC) and breast cancer cells which stably express exogenous estrogen receptors (ER). The anti-estrogenic compounds 4-hydroxy-tamoxifen (HT) and ICI 164384 (ICI) have different effects on the growth of the ER-transfectants. HT is a potent growth inhibitor, while ICI has no effect by itself but is able to block the anti-proliferative effects of E and HT. In order to elucidate the mechanism by which E or HT-bound ER inhibit cell growth, we have evaluated the effects of these compounds on the growth of HMEC stably expressing ER with mutations or deletions in the N-terminal A/B domain, the DNA-binding domain (DBD), and the C-terminal ligand-binding domain. These studies revealed that E and HT require different structural domains of the ER for their anti-proliferative activities. The N-terminal A/B domain is required for HT-, but not E-dependent growth inhibition. The DNA-binding domain of the ER is not essential for HT-mediated anti-proliferative effects, but is important for E-dependent activity. The effect of ER mutations on the ligand-inducible expression of the endogenous progesterone receptor (PR) and pS2 genes was also evaluated. Neither gene was induced in the cells containing the ER mutated in the DBD, even though cell growth was inhibited. These results suggest that E and HT use different pathways to elicit their anti-proliferative effects and that this occurs via modulation of genes that are controlled by mechanisms different from those important for activation of the PR and pS2 genes.
...
PMID:Different estrogen receptor structural domains are required for estrogen- and tamoxifen-dependent anti-proliferative activity in human mammary epithelial cells expressing an exogenous estrogen receptor. 944 40

Estrogens stimulate the growth of a majority of estrogen receptor (ER)-positive breast cancer cells. In contrast, estradiol exerted a 75% inhibition of DNA synthesis in the MCF-10AE(wt5) cell line, obtained by the transfection of the ER gene into a normal breast epithelial cell line, MCF-10A. The estradiol-mediated growth inhibitory effect was reversed by ICI 164384, a pure anti-estrogen. Analysis of cell cycle by flow cytometry showed a significant increase of G1 cells by estradiol treatment compared to controls. To understand the mechanism of action of estradiol on MCF-10AE(wt5) cells, we examined the level of a cyclin dependent kinase inhibitor (CKI), p21, by Western blot analysis. Our results showed a 5- to 10-fold increase in the level of p21 in estradiol-treated MCF-10AE(wt5) cells compared to controls. ICI 164384 reversed estradiol-mediated induction of p21. Northern blot analysis of p21 mRNA indicated that estradiol stimulated its message in MCF-10AE(wt5) cells. Analysis of a panel of 6 breast cancer cell lines showed the absence of p21 protein, whereas it was present at a very low level in MCF-10A cells. Comparison of p21 in MCF-10A and MCF-10AE(wt5) cells showed an abundance of p21 in the ER-transfected cells. However, this p21 appears to be inactive in the absence of estradiol. These results suggest a p21-mediated pathway as a possible mechanism for the growth inhibitory effects of estradiol on at least a subset of ER-transfected cell lines.
Breast Cancer Res Treat 1998 Jan
PMID:Induction of p21 (CIP1/WAF1/SID1) by estradiol in a breast epithelial cell line transfected with the recombinant estrogen receptor gene: a possible mechanism for a negative regulatory role of estradiol. 949 6

Tamoxifen (TAM), the only antiestrogen currently available for the endocrine therapy of breast cancer behaves as a mixed agonist/antagonist of estrogen action, thus limiting its therapeutic potential. We report the binding characteristics of a novel series of nonsteroidal antiestrogens to the rat uterine estrogen receptor. As measured by competition studies, the affinity of EM-652, the active metabolite of the prodrug EM-800, for the estrogen receptor is 7-11 times higher than that of 17beta-estradiol (E2), ICI 182780, and hydroxy-tamoxifen (OH-TAM), the active metabolite of Tamoxifen. EM-652 is 20x more potent than ICI 164384 and Droloxifene while it is 400 times more potent than Toremifene in displacing [3H]E2 from the rat uterine estrogen receptor. On the other hand, the prodrug EM-800 and Tamoxifen have respectively 150-fold and 410-fold less affinity for the estrogen receptor than the pure antiestrogen EM-652. No significant binding of EM-652, EM-800, TAM or OH-TAM was observed to the rat uterine progesterone receptor at concentrations up to 10,000 nM except for TAM that caused a 50% displacement of labeled R5020 at 4000 nM. No significant binding of EM-652 or EM-800 was observed on the rat ventral prostate androgen receptor or the rat uterine progesterone receptor. The present data demonstrate the high affinity and specificity of the new antiestrogen, EM-652, for the rat uterine estrogen receptor. The antiestrogen EM-652 thus becomes the compound having the highest known affinity for the estrogen receptor. Due to its unique potency and its pure antiestrogenic activity already demonstrated in many systems, this antiestrogen could well offer an important advance for the endocrine therapy of breast cancer, uterine cancer, and other estrogen-sensitive diseases in women.
...
PMID:Binding characteristics of novel nonsteroidal antiestrogens to the rat uterine estrogen receptors. 960 15

The pineal hormone, melatonin, inhibits proliferation of estrogen receptor (ER)-positive MCF-7 human breast cancer cells, modulates both ER mRNA and protein expression, and appears to be serum dependent, indicating interaction between melatonin and serum components. To examine the effects of melatonin on ER activity, ER transactivation assays were performed by transiently transfecting MCF-7 cells with an ERE-luciferase reporter construct. MCF-7 cells pre-treated with melatonin for as little as 5 min followed by either epidermal growth factor (EGF) or insulin resulted in the estrogen-independent transactivation of the ER. None of the compounds when used alone transactivated the ER. The ability of melatonin and EGF to transactivate the ER was abolished by the addition of the antiestrogen, ICI 164384, suggesting that melatonin and EGF co-operate to transactivate the ER. The modulation of ER transactivation was associated with changes in mitogen activated protein kinase activity and ER phosphorylation. This ER transactivation was blocked by pertussis toxin, a Galpha i-protein-coupled receptor inhibitor, suggesting cross talk between the G-protein-coupled melatonin receptor pathway and the EGF/insulin tyrosine kinase receptor pathways in modulating ER transactivation. Exactly how the ability of melatonin in combination with EGF to transactivate the ER relates to melatonin's observed growth suppressive effects is not clear. It is possible that, although melatonin and EGF transactivate the ER, this transactivation does not result in the full transcription of estrogen-responsive genes, but rather, makes the ER refractory to activation by estradiol, thus, blocking the mitogenic actions of estradiol.
...
PMID:Estrogen receptor transactivation in MCF-7 breast cancer cells by melatonin and growth factors. 972 86

The development of endocrine resistance in previously sensitive, estrogen receptor-positive breast cancers is a major limitation in the treatment of breast cancer. Because antiestrogens have a cell cycle-specific action on breast cancer cells and influence the expression and activity of several cell cycle-regulatory molecules, the development of aberrant cell cycle control mechanisms is a potential mechanism by which cells might develop resistance to antiestrogens. We postulated that overexpression of cyclin D1, which is a common feature of breast cancer, may confer antiestrogen resistance. We addressed this question in vitro by testing the ability of ectopic cyclin D1 overexpression to overcome the growth-inhibitory effects of tamoxifen and the pure steroidal antiestrogens, ICI 164384 and ICI 182780, in T-47D and MCF-7 human breast cancer cells. In cells stably transfected with a human cyclin D1 cDNA under the control of a metal-inducible metallothionein promoter, cyclin D1 expression was increased 2-4-fold following treatment with zinc. Despite the continued presence of antiestrogen, cyclin D1 induction resulted in the formation of active cyclin D1/Cdk4 complexes, concurrent hyperphosphorylation of the retinoblastoma protein, and entry into S phase of cells previously arrested in G1. Elevated cyclin D1 protein levels were first detected 3 h after treatment with zinc, and the proportion of cells in S phase began to increase 6 h later. The S-phase fraction increased 2-3-fold from 13 to 17% in cells treated with antiestrogen alone, to a peak of 33-38% 15 h after zinc treatment. Both the cyclin D1 protein level and the proportion of cells in S phase increased with increasing concentrations of zinc. We conclude that the ectopic overexpression of cyclin D1 reverses the growth-inhibitory effect of antiestrogens in estrogen receptor-positive breast cancer cells, providing a potential mechanism for clinical antiestrogen resistance.
...
PMID:Inducible overexpression of cyclin D1 in breast cancer cells reverses the growth-inhibitory effects of antiestrogens. 981 58

Estrogen receptor (ER)-negative breast carcinomas are often difficult to treat as they do not respond to hormone therapy. In an attempt to determine if expressing the human estrogen receptor in an ectopic manner could restore the hormone responsiveness of these cells, we have expressed the human ER in ER-negative MDA-MB 231 breast cancer cells using a recombinant adenovirus gene delivery system that allows high level expression of ER in essentially all cells. In these cells, the ER was correctly translated, had a wild type hormone binding affinity (Kd = 0.6 nM), bound well to estrogen response element-containing DNA, and showed an activation pattern of estrogen response element-reporter gene activity by estrogen and antiestrogens very similar to that observed in MCF-7 breast cancer cells containing endogenous ER (stimulation by estrogen, no stimulation by the antiestrogens trans-hydroxytamoxifen or ICI 164384, and blockade of estradiol stimulation by trans-hydroxytamoxifen or ICI 164384). Intriguingly, estradiol stimulation of these cells was also able to induce expression of pS2, an estrogen regulated gene considered to be a favorable prognostic marker for endocrine therapy in ER-positive breast cancer cells. Expression of the ER had no effect by itself on the proliferation rate of MDA-MB 231 cells. However, treatment of the ER-containing cells with estradiol or with the pure antiestrogen ICI 164 384 suppressed proliferation of the cells while the antiestrogen trans-hydroxytamoxifen had little effect on proliferation; and cotreatment with trans-hydroxytamoxifen reversed the estradiol- or ICI 164 384-evoked suppression of proliferation. To understand the mechanism underlying the inhibition of proliferation by estradiol, we examined the expression of several growth related endogenous genes. c-Myc protooncogene expression was strongly inhibited by treatment with estradiol as was expression of BRCA1 and BRCA2 genes, which is in agreement with their mitogenic-dependent expression, while expression of beta-actin, a housekeeping gene, was not affected by hormone treatment. Together, these data suggest that reexpressing the human ER in breast cancer cells that no longer express this protein renders them sensitive to hormone treatment. The ability of the antiestrogen ICI 164 384 to suppress the proliferation of ER-negative breast cancer cells that reexpress ER might be useful ultimately as an endocrine gene therapy approach for controlling the growth of ER-negative breast cancer cells. The application of recombinant adenoviruses expressing the human ER presents interesting features which might be used as a basis for designing more powerful and effective treatments for ER-negative breast cancers.
...
PMID:Expression of human estrogen receptor using an efficient adenoviral gene delivery system is able to restore hormone-dependent features to estrogen receptor-negative breast carcinoma cells. 1037 22


<< Previous 1 2 3 4 Next >>

---