UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The critical mechanisms responsible for antiestrogen resistance have not yet been elucidated. We previously established a breast cancer cell line, KPL-1, derived from a patient with recurrent disease which appeared under tamoxifenadministration. In a previous study, we suggested that this cell line is estrogen receptor (ER)-positive but tamoxifen-resistant. In the present study, the effects of a pure antiestrogen, ICI 182,780, on this cell line were investigated. Although tamoxifen inhibited neither cell growth nor estradiol-stimulated transcriptional activity in vitro, ICI 182,780, significantly inhibited both of them. Tamoxifen and ICI 182,780 were then administered to female nude mice bearing KPL-1 tumors. Tamoxifen had no effect on tumor growth, but ICI 182,780 unexpectedly stimulated it (p = 0.022). Estradiol tended to inhibit tumor growth (p = 0.198). Immunohistochemical analysis revealed that ICI 182,780 significantly increased the Ki6-labeling index (p<0.001) but estradiol decreased it (p = 0.035). To explore the possible mechanisms of these phenotypes, the mRNA levels of ER-alpha,ER-beta, transforming growth factor-beta1, fibroblast growth factor (FGF)-1 and FGF-4 in KPL-1 cells were compared with those in other ER-positive human breast cancer cell lines by reverse-transcription polymerase chain reaction. FGF-1 was overexpressed only in KPL-1 cells. This cell line is the first breast cancer cell line to be growth-stimulated by ICI 182,780 in vivo. Paracrine interaction between tumor cells and stromal cells mediated by growth factors, such as FGF-1, might be a key factor to explain the unique hormone responsiveness of KPL-1 cells.
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PMID:A pure antiestrogen, ICI 182,780, stimulates the growth of tamoxifen-resistant KPL-1 human breast cancer cells in vivo but not in vitro. 985 99

Two types of endocrine therapy that have been successfully applied to patients with hormone-dependent breast cancer are the non-steroidal antiestrogen tamoxifen, and inhibitors of aromatase, the enzyme that synthesizes estrogens. The major drawback with tamoxifen is that it acts as a partial estrogen-agonist and this is believed to mediate, at least in part, acquired tumor resistance to the drug as well as endometrial hyperplasia and carcinoma in some patients. The newer and more potent antiestrogen ICI 182,780 is a steroidal molecule that is devoid of estrogenic activity. We now report that ICI 182,780 is also an inhibitor of aromatase activity in fibroblasts isolated from the normal human breast as well as other carcinoma cell lines that express aromatase (MCF-7Ca breast cancer and JEG-3 choriocarcinoma). ICI 182,780 (1 microM) did not affect aromatase activity levels in human placental microsomes and only inhibited aromatase activity in each of the cell lines following a prolonged incubation period. In the fibroblasts, inhibition of aromatase activity by ICI 182,780 was shown to be time and dose-dependent. In contrast, tamoxifen and 17beta-estradiol were shown to have no effect on aromatase activity levels. ICI 182,780 inhibited aromatase activity levels with IC50 values of 16.80 nM in MCF-7Ca cells, 125.50 nM in JEG-3 cells and 386.1 nM in breast fibroblasts. These values were compared to those for known aromatase inhibitors, and in each of the cell lines the order of potency was letrozole>4-OHA>anastrozole>ICI 182,780. The inhibition of aromatase activity by ICI 182,780 was sustained even after the antiestrogen was removed from the cells indicating that ICI 182,780 may be remaining bound to the enzyme. Although ICI 182,780 had no effect on the proliferation of the fibroblasts, or JEG-3 cells, it significantly inhibited the growth of MCF-7Ca cells. This growth inhibition appeared to be due to the antiestrogenic activity of ICI 182,780 and not to its aromatase inhibiting effects. ICI 182,780 did not inhibit aromatase activity by down-regulating levels of the aromatase transcript. These results show that in addition to being a potent antiestrogen, ICI 182,780 is also an inhibitor of cellular aromatase activity, and suggest that by interfering with the actions of estrogen by two distinct mechanisms, ICI 182,780 may be a suitable drug for treating patients with hormone-dependent breast cancer.
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PMID:The steroidal antiestrogen ICI 182,780 is an inhibitor of cellular aromatase activity. 988 86

The antitumor effects of an experimental chemoendocrine therapy combining a new pure antiestrogen ICI 182780 and 5-fluorouracil (5-FU) were studied on MCF-7 human breast cancer cells implanted in nude mice. ICI 182780 had a dose-dependent antitumor activity, which was potentiated by the concomitant use of 5-FU. When compared with the control group, the estrogen receptor (ER) level in the ICI 182780 group was lower and that in the combination group was markedly lower. Cell cycle analysis by flow cytometry (FCM) resulted in a lower percentage of S-phase cells (%S) in the treated mice. No significant difference was observed in the 5-FU concentrations in tumor cells, while the 5-FU content in RNA was significantly higher in the combination group. The changes in free thymidylate synthetase (TS) concentration indicated TS synthesis after the administration of 5-FU to be more greatly suppressed in the combination group than in the 5-FU group. These results suggest that ICI 182780 and 5-FU exert their combination effect mainly on ER-positive cells, and that the suppression of TS synthesis in tumor cells and the potentiation of the 5-FU-induced metabolic dysfunction of RNA are thus involved in the mode of action of this combination therapy.
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PMID:Effects of experimental chemoendocrine therapy with a combination of a pure antiestrogen and 5-fluorouracil on human breast cancer cells implanted in nude mice. 1003 Jul 40

Breast cancer is the most frequent cancer in women while it is the second cause of cancer death. Estrogens are well recognized to play the predominant role in breast cancer development and growth and much efforts have been devoted to the blockade of estrogen formation and action. The most widely used therapy of breast cancer which has shown benefits at all stages of the disease is the use of the antiestrogen Tamoxifen. This compound, however, possesses mixed agonist and antagonist activity and major efforts have been devoted to the development of compounds having pure antiestrogenic activity in the mammary gland and endometrium. Such a compound would avoid the problem of stimulation of the endometrium and the risk of endometrial carcinoma. We have thus synthesized an orally active non-steroidal antiestrogen, EM-652 (SCH 57068) and the prodrug EM-800 (SCH57050) which are the most potent of the known antiestrogens. EM-652 is the compound having the highest affinity for the estrogen receptor, including estradiol. It has higher affinity for the ER than ICI 182780, hydroxytamoxifen, raloxifene, droloxifene and hydroxytoremifene. EM-652 has the most potent inhibitory activity on both ER alpha and ER beta compared to any of the other antiestrogens tested. An important aspect of EM-652 is that it inhibits both the AF1 and AF2 functions of both ER alpha and ER beta while the inhibitory action of hydroxytamoxifen is limited to AF2, the ligand-dependent function of the estrogen receptors. AF1 activity is constitutive, ligand-independent and is responsible for mediation of the activity of growth factors and of the ras oncogene and MAP-kinase pathway. EM-652 inhibits Ras-induced transcriptional activity of ER alpha and ER beta and blocks SRC-1-stimulated activity of the two receptors. EM-652 was also found to block the recruitment of SRC-1 at AF1 of ER beta, this ligand-independent activation of AF1 being closely related to phosphorylation of the steroid receptors by protein kinase. Most importantly, the antiestrogen hydroxytamoxifen has no inhibitory effect on the SRC-1-induced ER beta activity while the pure antiestrogen EM-652 completely abolishes this effect, thus strengthening the need to use pure antiestrogens in breast cancer therapy in order to control all known aspects of ER-regulated gene expression. In fact, the absence of blockade of AF2 by hydroxytamoxifen could explain why the benefits of tamoxifen observed up to 5 years become negative at longer time intervals and why resistance develops to tamoxifen. EM-800, the prodrug of EM-652, has been shown to prevent the development of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat, a well-recognized model of human breast cancer. It is of interest that the addition of dehydroepiandrosterone, a precursor of androgens, to EM-800, led to complete inhibition of tumor development in this model. Not only the development, but also the growth of established DMBA-induced mammary carcinoma was inhibited by treatment with EM-800. An inhibitory effect was also observed when medroxyprogesterone was added to treatment with EM-800. Uterine size was reduced to castration levels in the groups of animals treated with EM-800. An almost complete disappearance of estrogen receptors was observed in the uterus, vaginum and tumors in nude mice treated with EM-800. EM-652 was the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro when compared with ICI 182780, ICI 164384, hydroxytamoxifen, and droloxifene. Moreover, EM-652 and EM-800 have no stimulatory effect on the basal levels of cell proliferation in the absence of E2 while hydroxytamoxifen and droloxifene had a stimulatory effect on the basal growth of T-47D and ZR-75-1 cells. EM-652 was also the most potent inhibitor of the percentage of cycling cancer cells. (ABSTRACT TRUNCATED)
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PMID:EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium. 1041 81

AKT1 (c-AKT, PKBalpha) is the cellular homolog of the protein-serine/threonine kinase oncogene, v-akt. AKT1 is activated through the insulin and platelet-derived growth factor signaling pathways in transfected fibroblasts, but little is known about the regulation of endogenous AKT1 in tumor cells. AKT1 levels were higher in a panel of human breast carcinoma cell lines than in breast epithelial cells, particularly those with higher HER2 expression. AKT1 activity was increased by either estradiol or IGF-I in estrogen-dependent MCF-7 cells, and both factors acted synergistically to increase AKT1 activity and promote cell proliferation. Stimulation of AKT1 activity by estradiol and IGF-I was blocked by the antiestrogen ICI 182780 and by the phosphatidylinositol-3-kinase inhibitor wortmannin. MCF-7 cells transfected with AKT1 exhibited partial estrogen- and IGF-I-independent growth and were more responsive to the combination of IGF-I and estradiol. AKT1-overexpressing MCF-7 cells were less sensitive to apoptosis induced by wortmannin. These findings suggest that AKT1 is a downstream effector of estrogen- and IGF-I-dependent proliferation and survival in hormone-responsive MCF-7 breast carcinoma cells.
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PMID:Role of AKT1 in 17beta-estradiol- and insulin-like growth factor I (IGF-I)-dependent proliferation and prevention of apoptosis in MCF-7 breast carcinoma cells. 1042 60

Expression of estrogen receptor beta (ER-beta) and its regulation by estradiol and anti-estrogens was analyzed in breast cancer cells. We determined that ER-beta is expressed in normal and tumor human breast tissue as well as in breast cancer cell lines. We observed moderate levels of ER-beta expression in both T47D and T47D-V22 (a T47D variant cell line) cells, in contrast with T47DCo (a T47D variant cell line) cells when compared to ER-alpha expression. While T47DCo (a T47D variant cell line), BT474, MDA-MB-231, MDA-MB-453, MDA-MB-468 and MCF-7 express low levels of ER-beta, other cell lines including the T47D-Y (a T47D variant cell line), MDA-MB-435, BT-549, and SKBr-3 cells express undetectable levels of ER-beta. Interestingly, ER-beta and ER-alpha are apparently not co-expressed in the breast tissue analyzed. Estradiol induced 30-40-fold increased ER-beta mRNA expression in T47D cells over control untreated cells. Moreover, the anti-estrogen, 4-hydroxy-tamoxifen (4OH-Tam) strongly inhibited estradiol induction of ER-beta expression, but had little or no effect on estradiol induction of ER-alpha. A pure anti-estrogen, ICI-182,780, completely abolished the ability of estradiol to up-regulate the expression of ER. In addition, both actinomycin D and cyclohexymide inhibited estradiol induction of ER-beta mRNA, indicating that de novo mRNA and protein synthesis are probably required for this induction. In summary, this study demonstrates that ER-beta is expressed in breast cancer, and it is regulated by estradiol. Moreover, the studies demonstrate that estradiol up-regulation of ER-beta mRNA in T47D cells can be abolished by anti-estrogens. Thus, ER-beta expression may serve as a prognostic, diagnostic and/or therapeutic marker for breast cancer. To the best of our knowledge, this is the first report regarding hormonal regulation of ER-beta in human mammary cells.
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PMID:Expression and regulation of estrogen receptor beta in human breast tumors and cell lines. 1060 11

The potential of aromatase (estrogen synthetase) within the breast to provide a significant source of estrogen mediating tumor proliferation is suggested by studies reporting 4- to 6-fold higher estrogen levels in tumors than in plasma of postmenopausal patients with breast cancer. Recent studies in our laboratory have identified aromatase and its mRNA in tumor epithelial cells using immunocytochemistry and in situ hybridization. In addition, significant aromatase activity, which was stimulated 7-fold by dexamethasone, was measured in metastatic cells isolated from a breast cancer patient. Increase in proliferation, as measured by proliferating cell nuclear antigen immunostaining in tumor sections and by thymidine incorporation into DNA in response to testosterone, was observed in histocultures of breast cancer samples. This latter effect could be inhibited by 4-hydroxyandrostenedione. These results imply that intratumoral aromatase has functional significance and may be an important target for successful inhibitor treatment of breast cancer patients. To investigate treatment strategies with aromatase inhibitors and antiestrogens, we developed an intratumoral aromatase model to simulate the hormone responsive postmenopausal breast cancer patient. Tumors of estrogen receptor positive human breast carcinoma cells (MCF-7) transfected with the human aromatase gene are grown in ovariectomized nude mice. These cells synthesize sufficient estrogen to stimulate tumor formation. We have utilized this model to investigate the effects on tumor growth of the antiestrogens, tamoxifen and ICI 182780, and the aromatase inhibitors, letrozole and anastrozole (arimidex), alone and in combination. Both the aromatase inhibitors and the antiestrogens were effective in suppressing tumor growth. However, letrozole was significantly more effective than the antiestrogens. When the aromatase inhibitors were combined with the antiestrogen, tamoxifen, tumor growth was suppressed to about the same extent as with the aromatase inhibitors alone. Furthermore, the results do not suggest any benefit from combining tamoxifen with the pure antiestrogen, ICI 182780. Thus sequential use of these agents is likely to be more advantageous to the patient in terms of longer duration of effective treatment.
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PMID:Aromatase inhibitors and their antitumor effects in model systems. 1073 Nov 10

The normal epithelial cell-specific 1 (NES1) gene encodes a serine protease which was found to be down-regulated in breast cancer. There is evidence that NES1 acts as a tumor suppressor gene in breast cancer cells. To further understand its role in breast tumorigenesis, we investigated the effect of estrogens, androgens, and progestins on NES1 gene expression, in the breast cancer cell line BT-474, at the transcription level. The reverse transcriptase polymerase chain reaction method was used to monitor changes in the NES1 mRNA. Our experiments showed that NES1 gene expression is up-regulated promptly in response to 17 beta-estradiol, 5 alpha-dihydrotestosterone (DHT) and norgestrel stimulation. NES1 gene mRNA started to increase 2 hours after estradiol stimulation and 8 hours after DHT stimulation. The stimulation of NES1 by estradiol can be dramatically blocked by the estrogen antagonists ICI 182,780 and 4-hydroxytamoxifen. Mifepristone (a synthetic antiprogestin) can partially block the up-regulation of the NES1 gene by norgestrel. Dose-response experiments indicated that the lowest stimulatory concentration of 17 beta-estradiol, DHT, and norgestrel is 10(-11) M, 10(-10) M, and 10(-10) M, respectively. The production of NES1 mRNA increased coordinately with increasing concentration of the stimulants. These results suggest that the NES1 gene is primarily regulated by estrogen, but also by androgen and progestin in the breast cancer cell line BT-474. It appears that NES1 may be involved in a pathway that counter balances the action of estrogens and androgens in steroid hormone responsive tissues.
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PMID:The normal epithelial cell-specific 1 (NES1) gene is up-regulated by steroid hormones in the breast carcinoma cell line BT-474. 1081 Mar 85

Onapristone (also referred to as ZK 98,299) is an antiprogestin that shares a number of structural similarities to mifepristone (RU-486) and other drugs in this class. While investigating the actions of antiprogestins on steroid hormone induced gene expression of angiogenic factors such as vascular endothelial growth factor (VEGF), we noted that onapristone alone induces VEGF transcript levels in the immature, ovariectomized rat uterus. In addition, onapristone induces expression of c-fos mRNA, which is induced by estrogens but not progestins in this target tissue. This induction of VEGF and c-fos by onapristone is inhibited by the antiestrogen ICI 182,780, but not by the antiprogestin RU-486. Both transcripts are very rapidly induced by onapristone, with maximal mRNA levels observed 3-6 h after in vivo administration of the drug. This time course is similar to that for induction of these genes by estrogenic hormones. Dose-response studies show that both these genes are maximally induced by a 2.5 mg/kg dose of onapristone following intra peritoneal injection. These results indicate that onapristone rapidly upregulates several genes normally under estrogenic regulation in the immature rat uterus. Importantly, this is the first report of the induction of a major angiogenic factor by an antiprogestin. Since an increase in vascularity increases tumor expansion and metastasis, the induction of angiogenesis and its regulatory factors such VEGF may be an important end-point to consider in the development and use of antiprogestins for the treatment of neoplastic disease.
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PMID:Induction of the angiogenic factor VEGF in the uterus by the antiprogestin onapristone. 1084 Jan 65

Antiestrogens are widely used for breast cancer treatment, where they act primarily by inhibiting the mitogenic action of estrogens on tumor cells. The effects of the pure antiestrogen ICI 182,780 on estrogen-regulated cell cycle phase-specific events were investigated here in synchronously cycling human breast cancer (HBC) cells. In early G(1)-arrested MCF-7 or ZR-75.1 cells, 17beta-estradiol (E2) induces rapid activation of the cyclin/Cdk/pRb pathway, as demonstrated by D-type G(1) cyclins accumulation during the first few hours of hormonal stimulation, followed by sequential accumulation of E, A and B1 cyclins and progressive pRb phosphorylation, as cells progress through the cell cycle. When added to quiescent cells together with E2, ICI 182,780 prevents all of the above hormonal effects. Interestingly, in mid-G(1) cells (2-8 h into estrogen stimulation) the antiestrogen causes rapid reversal of hormone-induced D-type cyclins accumulation and pRb phosphorylation, and still fully inhibits G(1)-S transition rate, while in late-G(1) cells it does not prevent S phase entry but still inhibits significantly DNA synthesis rate, S-phase cyclins accumulation and pRb hyperphosphorylation. These results indicate that pure antiestrogens prevent multiple estrogen-induced cell cycle-regulatory events, each timed to allow efficient G(1) completion, G(1)-S transition, DNA synthesis and cell cycle completion.
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PMID:The antiestrogen ICI 182,780 inhibits proliferation of human breast cancer cells by interfering with multiple, sequential estrogen-regulated processes required for cell cycle completion. 1094 Apr 98

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